Onur ATEŞ 20223512006 BEN503|MiniReview

Mini Review: The Relationship between Apoptosis and PRDX1

1. Abstract:

apoptosis is a natural process of cell death that helps maintain homeostasis in an organism by eliminating
excess or damaged cells. It plays a crucial role in the early development and differentiation of embryos,
as well as in preventing the accumulation of non-functional cells in the tissue. Dysregulation of apoptosis
can lead to the accumulation of cells with genetic mutations that can potentially progress to the
development of malignant neoplasms or other pathological conditions. The regulation of apoptosis is
controlled by a complex network of pathways, and during the apoptotic process, a number of
biochemical changes and morphological transformations occur sequentially. Peroxiredoxins (PRDXs)
are enzymes that act in defense against oxidative stress by catalyzing the reduction of H2O2, alkyl
hydroperoxides, and peroxynitrite to water, alcohol, and nitrite respectively. They are considered the
most important and widespread enzymes that scavenge peroxides and peroxynitrite in all of biology and
are present in all three branches of life: Archaea, Bacteria, and Eukaryotes. PRDXs have been classified
into three subgroups based on their functional site sequence similarity.PRDX1 is an enzyme that is
widely distributed across all three branches of life and plays a crucial role in protecting cells from
oxidative stress. It has been found to be overexpressed in many types of cancer, including liver cancer,
and its overexpression has been shown to inhibit the intrinsic pathway of apoptosis, which is a natural
process of cell death that helps maintain homeostasis in an organism by eliminating excess or damaged
cells. The research suggests that PRDX1 blocks the cleavage of caspase 3 and caspase 9, which are
enzymes needed to activate apoptosis, and downregulates PARP-1, a protein responsible for cell death,
DNA repair and transcription of inflammatory-related genes. Additionally, PRDX1 influences the
intrinsic pathway of apoptosis by increasing the level of anti-apoptotic Bcl2 and decreasing the level of
pro-apoptotic Bax, while also enhancing the expression of Drp1, Fis1, and Dyn2, which are important
for fission of mitochondria. The levels of Cytochrome C and Apaf-1, which participate in the formation
of the "Apoptosome" complex in the intrinsic pathway of apoptosis, were also found to be elevated when
PRDX1 levels were decreased. Overall, the research suggests that PRDX1 plays a crucial role in
inhibiting the intrinsic pathway of apoptosis, allowing cancer cells to ignore their fate and survive.

Keywords: Apoptosis, Intrinsic and Extrinsic Apoptosis, PRDXs, PRDX1, Hepatocellular Carcinoma

2. Introduction

The primary goal for a cell is to maintain its survival throughout its lifetime. Regulation of cell
proliferation and death mechanisms is crucial for maintaining a balance between living and dead cells
in the body. One such mechanism of cell death is apoptosis, also known as programmed cell death. It is
a natural process by which cells die in a controlled and orderly manner under certain conditions.
Apoptosis plays an important role in maintaining homeostasis in an organism by eliminating excess or
damaged cells that are no longer needed during development, growth, or aging. It helps to keep the
number of cells in a tissue at a constant level and ensures the proper functioning of the body (Elmore,
2007). Apoptosis plays a crucial role in the early development and differentiation of embryos, helping
to create a fully formed organism. The term "apoptosis" was first coined by Kerr et al. in 1972 to describe
a specific type of cell death. However, it was not until 1999 that the mechanisms of apoptosis were
understood through studies on the development of the nematode Caenorhabditis elegans (Kiraz et al.,
2016).

Apoptosis is a fundamental cellular defense mechanism against damaged, stressed, or stimulated cells
by various agents to prevent the accumulation of non-functional cells in the tissue. Dysregulation of
apoptosis can lead to the accumulation of cells with genetic mutations that can potentially progress to

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the development of malignant neoplasms or other pathological conditions such as autoimmune

disorders, HIV/AIDS, or certain neurodegenerative disorders (Ellis and Horvitz, 1999). However, while
apoptosis is the best understood and most well-defined form of programmed cell death, there are various
other types of cellular death mechanisms such as pyroptosis, necrosis, or autophagy, and it's possible
that other mechanisms have yet to be discovered (Kiraz et al., 2016). The regulation of apoptosis is
controlled by a complex network of pathways, including various gene families, that coordinate the
specific morphological and biochemical changes in cells during the apoptotic process.

Peroxiredoxins (PRDXs) are a family of enzymes that help regulate peroxide levels within cells. They
are found in a variety of organisms and play a number of important functions. The PRDX family in
humans consists of six isoforms, called PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, and PRDX6. These
enzymes are divided into two subgroups based on the cysteine residues involved in catalysis: 2-Cys and
1-Cys. PRDXs protect cells by breaking down hydrogen peroxide, organic hydroperoxides, and
peroxynitrite. They can also act as a molecular chaperone, protecting proteins from oxidative injury or
degradation. Recent studies have shown that PRDXs play a crucial role in the regulation of various
cellular processes, including proliferation, differentiation, and apoptosis. Research has also shown that
PRDXs are involved in different types of diseases such as cancer, inflammatory-related diseases, and
neurodegenerative diseases. Because PRDXs can eliminate the reactive oxygen species produced by
rapidly dividing tumor cells, changes in the expression of these proteins can significantly affect tumor
cell proliferation (Lu et al., 2020).

3. 1 Morphological and Biochemical Changes in Apoptosis

During the apoptotic process, a number of biochemical changes and morphological transformations
occur sequentially. These changes can be observed under a microscope as early as the initiation stage of
the process and persist until the apoptotic cell death is complete. These changes include but are not
limited to, shrinkage of the cells, condensation of chromatin, and fragmentation of nuclei, among others.
The morphological cascade of events that occur during apoptosis, such as the aggregation of cytoplasmic
filaments, nuclear condensation, cellular fragmentation, and plasma membrane blebbing, ultimately lead
to the formation of apoptotic bodies. All of the morphological characteristics of apoptosis can be broadly
categorized into three categories: changes that occur in the nucleus, changes in the cell membrane and
cytosol, and changes that happen in the mitochondria (Elmore, 2007). During apoptosis, several nuclear
changes occur that can be observed with light and fluorescence microscopy, such as chromatin
condensation, DNA fragmentation, and nuclear fragmentation. These changes start with the breaking of
connections between the apoptotic cell and its surrounding cells, a process that leads to the formation of
apoptotic bodies and prevents the initiation of inflammatory reactions. These bodies are rapidly
phagocytized by neighboring cells without triggering any further inflammatory response. Mitochondria
also play a crucial role in the process, interacting with various apoptotic and anti-apoptotic proteins and
releasing signaling molecules that coordinate the events of apoptosis (Ferri and Kroemer, 2001;
Rosenblatt et al., 2001).

Apoptosis is characterized by several morphological changes in the nucleus, the most prominent being
chromatin condensation and nuclear fragmentation. These changes eventually lead to pyknosis, which
is irreversible chromatin condensation that signifies cell death, followed by karyorrhexis, or nuclear
fragmentation, the last event in the nucleus during apoptosis. Additionally, the fragmentation of double-
stranded DNA into 180-200 base pair sequences is an essential hallmark of nuclear events during
apoptosis, which is mediated by caspase proteins and other enzymes such as DNA fragmentation factors
(DFFs) and endonucleases. Caspases are also responsible for DNA repair during replication, as well as
the termination stage of apoptosis. These nuclear changes observed by electron microscopy or light
microscopy make it easy to determine the apoptotic process (Liu et al., 1998). Once apoptosis is initiated

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in cells, they lose their connections with neighboring cells, the membrane shrinks and the cell's cytosolic
contents are packaged into apoptotic bodies. These bodies are recognized and eliminated by phagocytic
cells that detect phosphatidylserine, a phospholipid normally found on the inner side of the cell
membrane but which is flipped to the outer membrane during apoptosis (Grimsley and Ravichandran,
2003). The process also results in the deactivation of the cytoplasmic scaffold proteins and cell junction
proteins, such as actin, β- catenin, spectrin, or Gas2, by cleavage, and the cell loses its integrity as a
result of caspases activity (Mashima et al., 1997).

Mitochondria play a complex and important role in the apoptotic process by providing various pro-
apoptotic signals and initiating a downstream cascade of apoptosis activation. The balance between pro-
apoptotic and anti-apoptotic molecules regulates cellular homeostasis and determines whether a cell
undergoes apoptosis or proliferation. Mitochondria are key players in releasing a number of important
apoptosis-inducing molecules, including cytochrome c, SMAC, apoptosis-inducing factor, and
endonuclease G as a result of the permeabilization of the mitochondrial membrane. Permeabilization is
triggered by pro-apoptotic B cell lymphoma (Bcl-2) family proteins, while the integrity of the
mitochondrial membrane is maintained by anti-apoptotic members of the Bcl-2 family. A number of
biochemical changes such as protein modifications/degradations, DNA and chromatin deterioration, and
synthesis of cell surface markers occur during apoptosis. Caspases are mainly responsible for these
changes, and their extensive capability to cleave certain molecules from one or more specific points
leads to degradation and inactivation of target proteins. Caspases also play a role in DNA fragmentation
process, by inhibiting the negative regulatory domains of specific proteins and activating the target
molecule (Kiraz et al., 2016).

3.2 Types of Apoptosis

Apoptosis, or programmed cell death, can be triggered through two distinct mechanisms. The intrinsic
pathway, which is primarily mediated by the release of a protein called cytochrome c from the
mitochondria. This initiates a chain reaction leading to the activation of specific enzymes called
caspases. The extrinsic pathway, on the other hand, is activated when a cell surface receptor called the
Fas death receptor receives a signal from the external environment. Both the intrinsic and extrinsic
pathways converge at the activation of caspases, ultimately leading to the destruction of specific cellular
proteins (Safe, 2015).

3.2.1 Intrinsic Apoptosis

The intrinsic pathway of apoptosis does not require a signaling from a receptor, and instead relies on
signals arising within the cell itself. This pathway can lead to the initiation of apoptosis in response to
both positive and negative stimuli. Positive stimuli, such as toxic materials, viral infections, and
radiation, directly activate the mediators of apoptosis, while negative stimuli, such as a loss of growth
factors or certain types of hormones, work by eliminating the factors that suppress apoptosis in the cells
(Elmore, 2007). DNA damage is also a major inducer of apoptosis as a mechanism to protect cells from
self-proliferation with an imperfect DNA sequence. Changes in the transmembrane potential of the
mitochondria, resulting from DNA damage or other types of apoptotic stimuli, cause the release of pro-
apoptotic proteins such as cytochrome c, Smad, or high-temperature requirement protein A2
(HtrA2)/Omi into the cytoplasm. These proteins activate a cascade of caspase proteins, leading to the
fragmentation of the nucleus and breaking of the nuclear membrane, which is the initial event for both
the intrinsic and extrinsic pathways of apoptosis. Caspase-3 then cleaves various proteins, leading to
DNA condensation, membrane blebbing, and other morphological changes that are regulated as a
common mechanism for both intrinsic and extrinsic triggers. The intrinsic apoptotic events are primarily
controlled by the Bcl-2 family of proteins and the p53 tumor suppressor protein, which plays a major

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role in the activation of the Bcl-2 family proteins, these can act as pro-apoptotic or anti-apoptotic and
also determine the integrity of the mitochondrial membrane (Kiraz et al., 2016).

3.2.2 Extrinsic Apoptosis

The extrinsic pathway of apoptosis is primarily triggered by signaling through membrane-bound death
receptors that are members of the tumor necrosis factor (TNF) superfamily. The initial signal is
generated by the interaction between ligands and cell membrane death receptors such as Fas
ligand/FasR, TNF/TNF R1, Apo2L/DR4, or TNF-related apoptosis-inducing ligand (TRAIL) R1. This
leads to the ligation of death domains on these receptors. The binding of Fas ligand to its receptor leads
to the binding of the adaptor protein Fas-associated death domain (FADD), while the TNF/tumor
necrosis factor receptor (TNFR) interaction causes the binding of TNFR-associated death domain
(TRADD), leading to the activation of pro-caspase-8. Pro-caspase-8 is activated autocatalytically by the
death-inducing signaling complex (DISC). Activated caspase-8 can either activate Bid, thus involving
the intrinsic pathway, or activate caspase-3 and caspase-7, leading to the same final pathway as intrinsic
stimuli. Bid is the pro-apoptotic member of the Bcl-2 family, which is a common molecule between
intrinsic and extrinsic pathways of apoptosis. Caspase-8 causes the cleavage and myristylation of the
cytoplasmic Bid protein, resulting in its movement to the mitochondria and the subsequent formation of
apoptosomes through the release of cytochrome c via Bak and Bax molecules. The extrinsic activation
of apoptosis can also be inhibited by two different ways, such as binding of FLICE-like inhibitory
protein (cFLIP) to FADD and pro-capase-8 and blocking their activity, or by inhibition of caspase-8
biogenesis by a protein named Toso which is firstly described in T cells (Kiraz et al., 2016).

4. 1 PRDXs

Peroxiredoxin (PRDXs) family proteins are one of the essential enzyme systems that act in the defense
against oxidative stress (Zhou et al., 1997).

PRDXs are a widely distributed group of enzymes that have been discovered in many organisms. They
act as a universal family of thiol-dependent peroxidases that catalyze the reduction of H2O2, alkyl
hydroperoxides and peroxynitrite to water, alcohol, and nitrite respectively (Bryk et al., 2000). They are
considered as the most important and widespread enzymes that scavenge peroxides and peroxynitrite in
all of biology. For a long time, their role was overshadowed by more well-known antioxidant enzymes
such as catalase and glutathione peroxidase, which were thought to be the main enzymes responsible for
protecting cells from hydroperoxides (Karplus, 2015). But now the importance of PRDXs in oxidative
stress defense is well established and they are considered as the backbone of the defense system against
oxidative stress.

PRDXs are different from catalase and glutathione peroxidase in that they do not require cofactors, such
as heme for catalase and selenium for GPx. They were first discovered in yeast and mammals around
27 and 25 years ago respectively and are present in all three branches of life: Archaea, Bacteria, and
Eukaryotes, highlighting the fundamental role that these enzymes play in protecting living organisms
from reactive oxygen species (ROS). Their presence in all three domains of life indicates that defense
against ROS has been essential for the evolution of living organisms. PRDXs have been classified into
three subgroups based on their functional site sequence similarity: Prx1/PRDX1, Prx5/PRDX5 and
Prx6/PRDX6. The distribution of PRDXs across different organisms demonstrates the widest biological
distribution for the Prx1/PRDX1 and Prx6/PRDX6 subfamilies, while the Prx5/PRDX5 subfamily
seems to be absent in archaea. The different subgroups of PRDXs vary in their oligomerization states,
conformational flexibility, and certain secondary structural elements. Additionally, most organisms have
multiple isoforms: for example, humans have six different isoforms of PRDX, which includes four

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PRDX1 subtypes, one PRDX5 subtype, and one PRDX6 subtype. PRDX1, PRDX2, PRDX3, PRDX5,
and PRDX6 are located in the cytosol, mitochondria, nuclei, and peroxisomes, while PRDX4 is mainly
present in the endoplasmic reticulum or secreted out of the cell (Nicolussi et al., 2017).

The ability of PRDXs to catalyze their reactions is critically dependent on a conserved cysteine (Cp)
residue that is located within the active site of the enzyme. This residue is contained within a universally
conserved Pxxx(T/S)xxC motif in the amino-terminal portion of the protein, and corresponds to Cys-47
in yeast cytosolic thioredoxin peroxidase I (cTPx I). The Cp residue is essential for the catalytic activity
of PRDX enzymes and is responsible for the reduction of peroxides and peroxynitrite, resulting in their
neutralization and protection of the cell from oxidative stress (Nelson et al., 2011). Out of the six human
PRDXs, five of them also contain an additional conserved cysteine residue in the carboxy-terminal
region, similar to Cys-170 in yeast thiol-specific antioxidant (TSA). This additional cysteine residue is
known as resolving cysteine (Cr) . Depending on the PRDX, the Cr may be located within the same
chain as the Cp residue or in another subunit chain. Because of this, human PRDXs are classified into
three classes: i) Typical 2-Cys PRDXs, which include PRDX1-4, ii) atypical 2-Cys PRDX and PRDX5,
and iii) 1-Cys PRDX and PRDX6. The resolving cysteine (Cr) is not essential for peroxidase activity,
but plays a key role in resolving a catalytic intermediate, by reducing disulfide bond of the intermediate
and promotes the turnover of PRDXs.

Out of the six human PRDXs, five of them also contain an additional conserved cysteine residue in the
carboxy-terminal region, similar to Cys-170 in yeast thiol-specific antioxidant (TSA). This additional
cysteine residue is known as resolving cysteine (Cr) . Depending on the PRDX, the Cr may be located
within the same chain as the Cp residue or in another subunit chain. Because of this, human PRDXs are
classified into three classes: i) Typical 2-Cys PRDXs, which include PRDX1-4, ii) atypical 2-Cys PRDX
and PRDX5, and iii) 1-Cys PRDX and PRDX6. The resolving cysteine (Cr) is not essential for
peroxidase activity, but plays a key role in resolving a catalytic intermediate, by reducing disulfide bond
of the intermediate and promotes the turnover of PRDXs (Rhee et al., 2001). The typical 2-Cys PRDXs
are composed of two identical subunits that each contain an active site, bringing the two redox-active
cysteines (Cp and Cr) in close proximity. These enzymes typically form obligate homodimers and have
two active sites. On the other hand, atypical 2-Cys PRDXs form an intramolecular disulfide intermediate
by reacting the amino-terminal sulfenic acid (Cys-47) with a carboxy-terminal cysteine residue (Cys-
151) of the same molecule, this intermediate is able to be reduced by thioredoxin. Unlike typical 2-cys
PRDXs these atypical PRDXs do not require another subunit to form a dimer, and have only one active
site within the monomeric protein.

PRDXs play a vital role in regulating various cellular physiological functions, including cell growth,
differentiation, apoptosis, embryonic development, lipid metabolism, and the immune response, as well
as maintaining cellular homeostasis. In recent years, a growing body of evidence has suggested that
PRDXs are also involved in carcinogenesis and the development of drug resistance in cancer. This
review focuses on the intricate relationships between oxidant balance and cancer, and provides an
overview of the involvement of PRDXs in tumor development and the emergence of resistance to
chemotherapy. PRDXs are crucial enzymes that play a key role in maintaining cellular redox balance,
and understanding how they contribute to cancer biology can aid in the development of new cancer
therapies (Nicolussi et al., 2017).

4.2 PRDX1 in Tumorigenesis

Cells have multiple systems in place to degrade peroxides, and the relative importance of these systems
is still a topic of ongoing research. PRDXs are a fascinating group of thiol-dependent peroxidases that
perform a wide range of functions under physiological conditions, including protecting cells from

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oxidative DNA damage and genomic instability, regulating cell signaling related to H2O2, and
influencing cell differentiation and proliferation, immune responses, and apoptosis. The diversity and
complexity of these functions emphasize the importance of PRDXs in maintaining cellular homeostasis
and the potential for PRDXs as targets for therapeutic intervention in disease states. A number of studies
have demonstrated that cancer cells often produce excessive levels of reactive oxygen species (ROS),
which can be caused by a loss of proper redox control. In recent years, researchers have focused on
exploring the role of PRDXs in the development of cancer. Abnormal levels of PRDXs, either increased
or decreased, have been observed in many types of human cancers. The changes in PRDX expression
levels in cancer cells suggest that these enzymes play an important role in cancer development, and
understanding their mechanism can help to develop new cancer therapies. Their alteration in expression
levels may be caused by genetic mutations, epigenetic modifications or other mechanisms. They can be
used as potential biomarkers for cancer diagnosis, prognosis, and drug resistance (Nicolussi et al., 2017).
Studies conducted using in vitro or in vivo models have shown that an increase in PRDX expression
may have different effects on cancer development, depending on the specific PRDX family member and
the context of the cancer. Some studies have shown that overexpression of certain PRDXs can inhibit
cancer growth, while others have shown that it can promote cancer growth. This may reflect the diversity
of PRDXs and the different cellular environments in which they function. It also highlights that
understanding the precise mechanisms by which PRDXs affect cancer development is complex and not
fully understood, and further research is needed to fully grasp the role of these enzymes in cancer
development and progression (Park et al., 2016).
4.2.1 Dual Effect of PRDX1 in Tumorigenesis
PRDX1 is widely distributed across different cell types and is present in high levels in many tissues.
The expression of PRDX1 is regulated both at the transcriptional level by the transcription factor nuclear
factor (erythroid-derived 2)-related factor 2 (NRF2) and at the post-transcriptional level through
processes such as degradation and deadenylation/polyadenylation. This allows for the fine-tuning of
PRDX1 levels in different cellular contexts, which may play a role in its dual effect on cancer
development (Kim et al., 2007; Neumann et al., 2009; Thélie et al., 2007).
4.2.2 Tumor Suppressor PRDX1
The tumor suppressor function of PRDX1 was first identified in a knockout mouse model, where the
absence of PRDX1 led to the development of hemolytic anemia and multiple tumors, including
mammary carcinomas. These studies suggested that the tumor-suppressive effects of PRDX1 may be
mediated by a reduction of c-Myc transcriptional activity or of the activity of the phosphatase and tensin
homolog (PTEN/AKT) pathway. This suggests that PRDX1 may play a role in regulating cellular
growth and proliferation, which may in turn impact cancer development. Which also highlights that
understanding the mechanism by which PRDX1 functions in cancer development is complex and not
fully understood and more research is needed to fully grasp its role in the disease (Cao et al., 2009; Egler
et al., 2005; Neumann et al., 2003). It has been proposed that PRDX1 exerts its protective effect by
oxidizing a specific cysteine residue located within the active site of the PTEN phosphatase, which
results in the reduction of the predisposition of PRDX1-deficient mice to develop mammary tumors
induced by Ras signaling. This suggests that PRDX1 plays a role in regulating the PTEN/AKT pathway,
which is commonly altered in cancer. This mechanism highlights that the activity of PRDX1 and its
redox regulation of the PTEN/AKT pathway and the Ras signaling could be a promising target for cancer
therapy (Cao et al., 2009). PRDX1 has been shown to have a protective role in breast cancer in estrogen-
receptor-positive cases by preventing oxidative stress-mediated reduction of estrogen receptor alpha.
Overexpression of PRDX1 in these types of cancer has been linked to a favorable prognosis (O’Leary
et al., 2014). In lung cancer, the tumor-suppressive effects of PRDX1 are thought to be mediated by
modulation of the ROS-mediated activation of the K-Ras/extracellular signal-regulated kinase (ERK)
pathway, this highlights how PRDX1 can modulate different signaling pathways which can affect the
development of cancer. These studies suggest that PRDX1 has a multifaceted role in cancer development

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and its expression and activity levels may have potential as a biomarker for prognosis and as a
therapeutic target (Park et al., 2013). PRDX1 has also been shown to have a role in promoting the
reactivation of the protein tyrosine phosphatase DEP-1 in human acute myeloid leukemia (AML). DEP-
1 is considered as a tumor suppressor that counteracts the action of the FLT3 ITD transforming kinase.
The activation of FLT3 ITD is often associated with AML, thus, the reactivation of DEP-1 by PRDX1
could help to inhibit the progression of the disease. This highlights the ability of PRDX1 to act as a
tumor suppressor in a context-specific manner. Studies show that PRDX1 can have a complex role in
cancer development, by modulating different signaling pathways and by acting as a tumor suppressor
or a promoter depending on the context and stage of the cancer (Godfrey et al., 2012).
4.2.3 Tumor Promoter PRDX1
PRDX1 has been found to promote the growth of various types of human cancer by interacting with
certain cancer-associated signaling pathways. It has been discovered to have increased levels in various
types of cancer such as lung (Kim et al., 2008), bladder (Quan et al., 2006), ovarian (Chung et al., 2010),
esophageal (Ren et al., 2013), cholangiocarcinoma (Zhou et al., 2015), liver (Sun et al., 2022, 2015),
pancreatic (Cai et al., 2015), mesothelioma (Kaarteenaho-Wiik et al., 2002) and glioblastoma (Svendsen
et al., 2011). In prostate cancer, PRDX1 overexpression leads to tumor growth and progression through
the regulation of tumor vasculature via the Toll-like receptor 4 (TLR4) and the increased expression of
the vascular endothelial growth factor (VEGF). Additionally, in certain lung cancer models, PRDX1's
role in promoting cancer is through the activation of c-Jun and AP-1 and the inhibition of E-cadherin
expression by the transforming growth factor β1 (TGFβ1). PRDX1 can also affect intracellular signaling
pathways that impact apoptosis, such as inhibiting apoptosis in thyroid cancer cells through the
inhibition of apoptosis signal-regulating kinase 1 (ASK1) activity or suppressing the activation of
caspases in human hepatoma, leading to resistance to tumor necrosis factor-α (TNFα)-related apoptosis-
inducing ligand (TRAIL). Decreased levels of PRDX1 in papillary thyroid carcinomas (PTCs) have
been found to be associated with the presence of the BRAF V600E mutation and lymph node metastasis,
indicating that PRDX1 reduction may be caused by mutated BRAF and is associated with a more severe
clinical outcome for PTCs (Nicolussi et al., 2017).
5. The Relationship between PRDX1 and Apoptosis
PRDX1 overexpression has been detected on many types of cancer which one of them is liver cancer,
Hepatocellular Carcinoma. It is one of the most common and most cause of death type of liver cancer.
PRDX1 occurrence is found to be inhibits mitochondrial (intrinsic) apoptosis in liver cancer. In an
experimental set up, the expression of PRDX1 upregulated by a vector construct and inhibited by
SiRNA. The cells with elevated PRDX1 level showed higher viability compared to the ones with
knocked down PRDX1. The study next investigates the levels of cleaved caspase 3 and caspase 9 on
these cells which they need to be cleaved in order to be activated so that they can induce apoptosis. The
western blot analysis showed that the levels of cleaved caspase 3 and 9 elevated in PRDX1 knockdown
cells so meaning the elevation of PRDX1 somehow blocks their cleavage so that they can not induce
apoptosis. PAPR-1 which is responsible in cell death, repair od DNA and transcription of inflammatory
related genes. PARP-1 also found be downregulated in PRDX1 elevated cells meaning that PRDX1
inhibits cells to undergo apoptosis by inhibiting PARP-1. Bcl2 family proteins as discussed below
divided into two based on their function, pro-apoptotic and anti-apoptotic. In western blot analysis, the
levels of Bcl2 (Anti-apoptotic) increases and Bax (pro-apoptotic) decreases when PRDX1 is
upregulated, and reverse happens when PRDX1 knockdown meaning that PRDX1 influences
mitochondrial pathway of apoptosis. Drp1, Fis1 and Dyn2 are the proteins that are important for fission
of mitochondria. The enhanced expression of these proteins reflects the apoptosis initiation and
abnormal mitochondrial functions. These protein levels are elevated when the levels of PRDX1
decreased which further analysis to check the levels of Cytochrome C and Apaf-1 which participate the
formation of “Apoptosome” complex in intrinsic pathway of apoptosis. Not surprisingly the levels of
these proteins also elevated with absence of PRDX1 with combining previous findings the PRDX1

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influences the intrinsic pathway of apoptosis to prevent the cell death so that cancer cells ignore their
destiny (Sun et al., 2022).
6. Conclusion
Apoptosis is a controlled cell death which is important for development and also maintaining
homeostasis by removing unwanted or unnecessary cells in the body. Induction of apoptosis is tried to
mediate by anticancer drugs for treatment of various cancers by creating a damage on the cells. PRDXs
family proteins are essential to remove peroxides inside the cells. PRDX1 is one of the member of
PRDXs family which is found to be upregulated in HCC. Upregulation of PRDX1 prevent cell to go
under intrinsic apoptosis due to PRDX1 effects on the apoptotic protein synthesis. So that PRDX1 can
be a molecular target for other cancer research as well.
References
Bryk, R., Griffin, P., and Nathan, C. (2000). Peroxynitrite reductase activity of bacterial
peroxiredoxins. Nature 407, 211–215.
Cai, C.Y., Zhai, L.L., Wu, Y., and Tang, Z.G. (2015). Expression and clinical value of peroxiredoxin-
1 in patients with pancreatic cancer. Eur. J. Surg. Oncol. 41, 228–235.
Cao, J., Schulte, J., Knight, A., Leslie, N.R., Zagozdzon, A., Bronson, R., Manevich, Y., Beeson, C.,
and Neumann, C.A. (2009). Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity. EMBO
J. 28, 1505.
Chung, K.H., Lee, D.H., Kim, Y., Kim, T.H., Huh, J.H., Chung, S.G., Lee, S., Lee, C., Ko, J.J., and
An, H.J. (2010). Proteomic identification of overexpressed PRDX 1 and its clinical implications in
ovarian carcinoma. J. Proteome Res. 9, 451–457.
Egler, R.A., Fernandes, E., Rothermund, K., Sereika, S., De Souza-Pinto, N., Jaruga, P., Dizdaroglu,
M., and Prochownik, E. V. (2005). Regulation of reactive oxygen species, DNA damage, and c-Myc
function by peroxiredoxin 1. Oncogene 24, 8038–8050.
Ellis, H.M., and Horvitz, H.R. (1999). Genetic control of programmed cell death in the nematode C.
elegans. Cell 44, 817–829.
Elmore, S. (2007). Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516.
Ferri, K.F., and Kroemer, G. (2001). Organelle-specific initiation of cell death pathways. Nat. Cell
Biol. 3.
Godfrey, R., Arora, D., Bauer, R., Stopp, S., Müller, J.P., Heinrich, T., Böhmer, S.A., Dagnell, M.,
Schnetzke, U., Scholl, S., et al. (2012). Cell transformation by FLT3 ITD in acute myeloid leukemia
involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ.
Blood 119, 4499–4511.
Grimsley, C., and Ravichandran, K.S. (2003). Cues for apoptotic cell engulfment: Eat-me, don’t eat-
me and come-get-me signals. Trends Cell Biol. 13, 648–656.
Kaarteenaho-Wiik, R., Lehtonen, S., Kinnula, V.L., Sormunen, R., Rhee, S.G., Kang, S.W., and Soini,
Y. (2002). Overexpression of peroxiredoxins I, II, III, V, and VI in malignant mesothelioma. J. Pathol.
196, 316–323.
Karplus, P.A. (2015). A primer on peroxiredoxin biochemistry. Free Radic. Biol. Med. 80, 183–190.
Kim, J.H., Bogner, P.N., Baek, S.H., Ramnath, N., Liang, P., Kim, H.R., Andrews, C., and Park, Y.M.
(2008). Up-regulation of peroxiredoxin 1 in lung cancer and its implication as a prognostic and
therapeutic target. Clin. Cancer Res. 14, 2326–2333.
Kim, Y.J., Ahn, J.Y., Liang, P., Ip, C., Zhang, Y., and Park, Y.M. (2007). Human prx1 gene is a target

Apoptosis and PRDX1 8 / 10

Onur ATEŞ 20223512006 BEN503|MiniReview

of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res. 67,
546–554.
Kiraz, Y., Adan, A., Kartal Yandim, M., and Baran, Y. (2016). Major apoptotic mechanisms and
genes involved in apoptosis. Tumour Biol. 37, 8471–8486.
Liu, X., Li, P., Widlak, P., Zou, H., Luo, X., Garrard, W.T., and Wang, X. (1998). The 40-kDa subunit
of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during
apoptosis. Proc. Natl. Acad. Sci. U. S. A. 95, 8461–8466.
Lu, E., Hu, X., Pan, C., Chen, J., Xu, Y., and Zhu, X. (2020). Up-regulation of peroxiredoxin-1
promotes cell proliferation and metastasis and inhibits apoptosis in cervical cancer. J. Cancer 11,
1170–1181.
Mashima, T., Naito, M., Noguchi, K., Miller, D.K., Nicholson, D.W., and Tsuruo, T. (1997). Actin
cleavage by CPP-32/apopain during the development of apoptosis. Oncogene 1997 149 14, 1007–
1012.
Nelson, K.J., Knutson, S.T., Soito, L., Klomsiri, C., Poole, L.B., and Fetrow, J.S. (2011). Analysis of
the peroxiredoxin family: using active-site structure and sequence information for global classification
and residue analysis. Proteins 79, 947–964.
Neumann, C.A., Krause, D.S., Carman, C. V., Das, S., Dubey, D.P., Abraham, J.L., Bronson, R.T.,
Fujiwara, Y., Orkin, S.H., and Van Etten, R.A. (2003). Essential role for the peroxiredoxin Prdx1 in
erythrocyte antioxidant defence and tumour suppression. Nature 424, 561–565.
Neumann, C.A., Cao, J., and Manevich, Y. (2009). Peroxiredoxin 1 and its role in cell signaling. Cell
Cycle 8, 4072–4078.
Nicolussi, A., D’Inzeo, S., Capalbo, C., Giannini, G., and Coppa, A. (2017). The role of
peroxiredoxins in cancer. Mol. Clin. Oncol. 6, 139.
O’Leary, P.C., Terrile, M., Bajor, M., Gaj, P., Hennessy, B.T., Mills, G.B., Zagozdzon, A., O’Connor,
D.P., Brennan, D.J., Connor, K., et al. (2014). Peroxiredoxin-1 protects estrogen receptor α from
oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast
cancer. Breast Cancer Res. 16, R79.
Park, M.H., Jo, M., Kim, Y.R., Lee, C.K., and Hong, J.T. (2016). Roles of peroxiredoxins in cancer,
neurodegenerative diseases and inflammatory diseases. Pharmacol. Ther. 163, 1.
Park, Y.H., Kim, S.U., Lee, B.K., Kim, H.S., Song, I.S., Shin, H.J., Han, Y.H., Chang, K.T., Kim,
J.M., Lee, D.S., et al. (2013). Prx i suppresses K-ras-driven lung tumorigenesis by opposing redox-
sensitive ERK/Cyclin D1 pathway. Antioxidants Redox Signal. 19, 482–496.
Quan, C., Cha, E.J., Lee, H.L., Han, K.H., Lee, K.M., and Kim, W.J. (2006). Enhanced expression of
peroxiredoxin I and VI correlates with development, recurrence and progression of human bladder
cancer. J. Urol. 175, 1512–1516.
Ren, P., Ye, H., Dai, L., Liu, M., Liu, X., Chai, Y., Shao, Q., Li, Y., Lei, N., Peng, B., et al. (2013).
Peroxiredoxin 1 is a tumor-associated antigen in esophageal squamous cell carcinoma. Oncol. Rep. 30,
2297.
Rhee, S.G., Kang, S.W., Chang, T.S., Jeong, W., and Kim, K. (2001). Peroxiredoxin, a Novel Family
of Peroxidases. IUBMB Life 52, 35–41.
Rosenblatt, J., Raff, M.C., and Cramer, L.P. (2001). An epithelial cell destined for apoptosis signals its
neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr. Biol. 11, 1847–1857.
Safe, S. (2015). Targeting apoptosis pathways in cancer - Letter. Cancer Prev. Res. 8, 338.
Sun, H.H., Li, Y.L., Jiang, H., Yin, X.H., and Jin, X.L. (2022). PRDX1 Influences The Occurrence

Apoptosis and PRDX1 9 / 10

Onur ATEŞ 20223512006 BEN503|MiniReview

and Progression of Liver Cancer by Inhibiting Mitochondrial Apoptosis Pathway. Cell J. 24, 657–664.
Sun, Y.L., Cai, J.Q., Liu, F., Bi, X.Y., Zhou, L.P., and Zhao, X.H. (2015). Aberrant expression of
peroxiredoxin 1 and its clinical implications in liver cancer. World J. Gastroenterol. 21, 10840.
Svendsen, A., Verhoeff, J.J.C., Immervoll, H., Brøgger, J.C., Kmiecik, J., Poli, A., Netland, I.A.,
Prestegarden, L., Planagumà, J., Torsvik, A., et al. (2011). Expression of the progenitor marker
NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta
Neuropathol. 122, 495–510.
Thélie, A., Papillier, P., Pennetier, S., Perreau, C., Traverso, J.M., Uzbekova, S., Mermillod, P., Joly,
C., Humblot, P., and Dalbiès-Tran, R. (2007). Differential regulation of abundance and deadenylation
of maternal transcripts during bovine oocyte maturation in vitro and in vivo. BMC Dev. Biol. 7, 125.
Zhou, J., Shen, W., He, X., Qian, J., Liu, S., and Yu, G. (2015). Overexpression of Prdx1 in hilar
cholangiocarcinoma: a predictor for recurrence and prognosis. Int. J. Clin. Exp. Pathol. 8, 9863.
Zhou, Y., Wan, X.Y., Wang, H.L., Yan, Z.Y., De Hou, Y., and Jin, D.Y. (1997). Bacterial scavengase
p20 is structurally and functionally related to peroxiredoxins. Biochem. Biophys. Res. Commun. 233,
848–852.

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