COLLEGE OF NATURAL SCIENCES

DEPARTMENT OF PLANT SCIENCES, MICROBIOLOGY & BIOTECHNOLOGY

BIOCHEMICAL PROCESSES IN ORGANISMS

GLYCOLYSIS & CANCER

GROUP 1

AWORI ANNA 23/U/07080/PS

AYELLA JOHNATHAN BONGOMIN 23/U/07171/PS
JJUKO LARRY ABRAHAM 23/U/08447/PS
NANYANGE CHRISTINE ANGELL 23/U/15342/PS
MWASE JOSHUA MARK 23/U/24242/PS
RUHANGARIYO EVELYN 23/U/17112/PS
NAMBALIRWA BENITAH 23/U/1104
KWEHAYO PRAISE 23/U/0657
ABUBAKARI FAHAD SSEMPEWO 22/U/22544
JEMIMAH RUTH ETIANG 20/U/11835/PS
GLYCOLYSIS & CANCER
Characteristics of Cancer Cells
Proliferate rapidly and continuously. Normal cells have strict regulatory mechanisms in
place to control their growth and division, but cancer cells have mutations that allow them
to bypass these controls and divide uncontrollably.
Evade the immune system. Normally, the immune system is able to recognize and destroy
abnormal cells before they have a chance to develop into cancer. However, cancer cells
have developed ways to evade detection by the immune system, allowing them to grow
and spread unchecked.
Cancer cells also have the ability to resist cell death, a process known as apoptosis.
Apoptosis is a natural mechanism by which damaged or abnormal cells are programmed
to die, but cancer cells have mutations that allow them to survive and continue to
proliferate.
Another characteristic of cancer cells is their ability to induce angiogenesis, the formation
of new blood vessels to supply nutrients and oxygen to growing tumors. Angiogenesis is a
critical step in the progression of cancer, as it allows tumors to grow larger and metastasize
to other parts of the body. Cancer cells produce signaling molecules that stimulate the
formation of new blood vessels, providing them with the nutrients and oxygen they need
to continue to proliferate and spread.
Cancer cells also have alterations in their metabolism, which allows them to survive and
thrive in the unique environment of a tumor. Cancer cells have a high rate of glucose
metabolism, known as the Warburg effect, which provides them with the energy they
need to sustain their rapid growth.

Carcinogenesis
Carcinogenesis is the process by which normal cells are transformed into cancer cells. This
complex process involves a series of genetic and epigenetic alterations that result in
uncontrolled cell growth and the ability to invade surrounding tissues. Understanding the
mechanisms underlying carcinogenesis is crucial for the development of effective cancer
prevention and treatment strategies.
One of the key factors in carcinogenesis is the accumulation of mutations in critical genes
that control cell proliferation and apoptosis. These mutations can be caused by a variety
of factors, including exposure to carcinogens such as tobacco smoke, ultraviolet radiation,
and certain chemicals. Once a critical gene is mutated, it can lead to uncontrolled cell
growth and the formation of a tumor.
Stages of Carcinogenesis
1. Initiation; mutation by virus, radiation, chemical, spontaneous.
2. Promotion; growth & division.
3. Progression; acquiring addition mutations for survival and proliferation.
4. Invasion & Metastasis.
The connection between glycolysis and cancer cells revolves around the second and third
stages of carcinogenesis.
Stage 2
Stage 2 of carcinogenesis is mainly driven by two genes in the human genome; oncogenes
and tumor suppressor genes.
Oncogenes are a crucial component of cancer development and progression, playing a
pivotal role in the transformation of normal cells into malignant ones. These genes are
typically involved in cell growth, division, and differentiation, and when mutated or
overexpressed, they can drive uncontrolled cell proliferation and tumorigenesis.
One of the most well-known oncogenes is the Ras gene, which is frequently mutated in a
variety of cancers, including lung, colon, and pancreatic cancer. The mutated Ras protein
is constitutively active, leading to dysregulated cell proliferation and survival. Other
commonly mutated oncogenes include the HER2 gene in breast cancer and the BCR-ABL
gene in chronic myeloid leukemia. These oncogenes drive tumorigenesis by promoting cell
growth, inhibiting apoptosis, and enhancing cell migration and invasion.
Tumor suppressor genes
Tumor suppressor genes play a crucial role in preventing the development of cancer. These
genes are responsible for regulating cell growth and division, and when they are mutated
or inactivated, cells can grow and divide uncontrollably, leading to the formation of
tumors. Tumor suppressor genes act as a protective barrier against cancer by inhibiting
the growth of abnormal cells and promoting cell death when necessary.
One of the most well-known tumor suppressor genes is the p53 gene, also known as the
"guardian of the genome." p53 is a transcription factor that plays a key role in inducing
cell cycle arrest, DNA repair, and apoptosis in response to cellular stress. Mutations in the
p53 gene are commonly found in many types of cancer and can lead to uncontrolled cell
growth and tumor formation.
Another important tumor suppressor gene is the retinoblastoma (RB) gene, which acts as
a checkpoint in the cell cycle by inhibiting the progression from the G1 to S phase. The RB
gene is frequently mutated or deleted in cancer cells, allowing them to bypass this
checkpoint and continue to divide uncontrollably.
In addition to p53 and RB, there are many other tumor suppressor genes that have been
identified, each playing a unique role in regulating cell growth and preventing cancer. For
example, the BRCA1 and BRCA2 genes are involved in DNA repair and maintenance, and
mutations in these genes are associated with an increased risk of breast and ovarian
cancer.

High expression of oncogenes leads to high expression of hypoxia inducible factor 1 (HIF
1).
Hypoxia inducible factor 1 (HIF-1) is a transcription factor that plays a critical role in
cellular response to hypoxia, or low oxygen levels. It is a heterodimeric protein composed
of two subunits, HIF-1α and HIF-1β. HIF-1α is the oxygen-responsive subunit, while HIF-
1β is constitutively expressed. Under normal oxygen conditions, HIF-1α is hydroxylated by
prolyl hydroxylase domain enzymes (PHDs), which marks it for degradation via the
ubiquitin-proteasome pathway. However, under hypoxic conditions, the activity of PHDs
is inhibited, leading to stabilization of HIF-1α and its translocation to the nucleus where it
dimerizes with HIF-1β to activate transcription of target genes.
One of the key functions of HIF-1 is to promote cellular adaptation to hypoxia by regulating
the expression of genes involved in processes such as angiogenesis, glycolysis, and
erythropoiesis. For example, HIF-1 upregulates the expression of vascular endothelial
growth factor (VEGF), which promotes the formation of new blood vessels to increase
nutrient delivery to hypoxic tissues. HIF-1 also enhances the expression of enzymes
involved in glycolysis, such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A
(LDHA), to switch to anaerobic metabolism for energy production in the absence of
oxygen.
HIF 1; increases glucose uptake by cells, increases production of glycolytic enzymes,
increases glycolysis. This leads to high production of pyruvate and excess energy.
How HIF-1 accomplishes these.
HIF-1 has been shown to increase the expression of glucose transporters, such as GLUT1
and GLUT3, which facilitate the uptake of glucose into cells. By enhancing the expression
of these transporters, HIF-1 ensures a steady supply of glucose for glycolysis, even under
conditions of limited oxygen availability. This increased glucose uptake is crucial for
sustaining cellular metabolism and energy production in hypoxic environments.
HIF-1 has been shown to play a critical role in upregulating the expression of several
enzymes involved in glycolysis. One such enzyme is hexokinase, which catalyzes the first
step of glycolysis by phosphorylating glucose to glucose-6-phosphate. Under hypoxic
conditions, HIF-1 enhances the expression of hexokinase, leading to increased glucose
uptake and utilization. This results in a higher rate of glycolysis and ATP production, which
is essential for cell survival under oxygen-deprived conditions.
HKII phosphorylates glucose to Glucose-6-Phosphate. G6P is impermeable through the
lipid bilayer cell membrane preventing the out diffusion of glucose.
Another enzyme that is regulated by HIF-1 in glycolysis is phosphofructokinase-2 (PFK-2),
PFK 2 converts Fructose-6-Phosphate to Fructose-2,6-Bisphosphate. F26bP influences the
activity of PFK 1 by overcoming its inhibition from negative feedback by excess ATP
produced in a normal cell. PFK 1 is an allosteric enzyme which catalyzes the conversion of
Fructose-6-Phosphate to Fructose-1,6-Bisphosphate. This is an irreversible reaction thus
makes glycolysis directional. It also increases efficiency of the process by creating more
stable phosphodiester bonds. Activation of HIF-1 leads to increased expression of PFK-1,
promoting the flux of glucose through glycolysis.
Additionally, HIF-1 enhances the expression of pyruvate kinase, the enzyme responsible
for the final step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate. By
upregulating pyruvate kinase, HIF-1 ensures the efficient conversion of glucose to
pyruvate.
Pyruvate dehydrogenase responsible for oxidation of pyruvate is inhibited by
phosphorylation modification in cancer cells luring the cells to only go one way of
anaerobic inhibition where pyruvate is converted to lactate (Warburg effect).
Warburg effect is when a cell’s level of glycolysis is more than the rate at which pyruvate
is being oxidized to Acetyl Co-A. This leads to high levels of lactate production by Lactate
dehydrogenase enzyme.
Lactate Influence to Cancer
HIF-1 also regulates the expression of lactate dehydrogenase, an enzyme that catalyzes
the conversion of pyruvate to lactate. Under hypoxic conditions, the upregulation of
lactate dehydrogenase by HIF-1 facilitates the production of lactate as an end product of
glycolysis.
Lactate provides acidic environment that kills Cytotoxic T-cells which are natural killer
cells. This promotes tumor invasion. lactate also interacts with the tumor
microenvironment to create a favorable environment for cancer growth. Lactate alters the
composition of the extracellular matrix and promote the recruitment of immune cells that
suppress anti-tumor immune responses. This immune-suppressive effect of lactate may
allow cancer cells to evade immune surveillance and establish a supportive niche for
tumor growth.
The tumor cells now are able and capable of excessive glucose uptake and glycolysis
providing enough energy for uncontrolled growth and division.
The Warburg effect
The Warburg effect is a phenomenon in cancer biology that was first described by Otto
Warburg in the 1920s. It refers to the observation that cancer cells have a unique
metabolic profile characterized by increased glucose uptake and fermentation of glucose
to lactate, even in the presence of oxygen. This shift in metabolism, known as aerobic
glycolysis, allows cancer cells to rapidly produce the energy and building blocks needed
for their rapid growth and proliferation.
One of the key features of the Warburg effect is the increased expression of glucose
transporters and glycolytic enzymes in cancer cells. This allows them to take up and
metabolize glucose at a much higher rate than normal cells.
Recent advances in technology, such as metabolomics and imaging techniques, have
allowed researchers to study the Warburg effect in greater detail and with higher
resolution. This has led to a better understanding of the metabolic rewiring that occurs in
cancer cells and has identified new potential targets for therapy.
The Cori cycle
The Cori cycle, also known as the lactic acid cycle, is a metabolic pathway that plays a
crucial role in the energy production. This cycle involves the interconversion of lactate and
glucose.
The liver can synthesize glucose through gluconeogenesis, using lactate as a precursor
molecule.
Key enzymes involved in the cycle include lactate dehydrogenase, which catalyzes the
conversion of lactate to pyruvate in the liver, and glucose-6-phosphatase, which catalyzes
the conversion of glucose-6-phosphate to glucose.
By recycling lactate back into glucose, cancer cells can sustain glycolytic metabolism and
promote their survival under conditions of metabolic stress.

Stage 3
Stage 3 involves progression of the cancer cells by acquiring additional mutations for
survival & proliferation.
Glucose-6-Phosphate joins the Pentose Phosphate Pathway. The Pentose Phosphate
Pathway (PPP), also known as the hexose monophosphate shunt, is a fundamental
metabolic pathway in all living organisms. The main function of the PPP is to generate
NADPH and pentose sugars, which are essential for biosynthetic processes and cellular
redox balance.
The PPP is especially important in cells that are actively dividing and synthesizing
macromolecules, such as rapidly growing tissues and cancer cells. NADPH generated by
the PPP is crucial for maintaining the reduced state of cellular components and serving as
a cofactor for various biosynthetic reactions, including fatty acid synthesis. Additionally,
the pentose sugars produced by the pathway can be used for nucleotide synthesis, DNA
replication, and other biosynthetic processes.
The PPP is a highly regulated pathway that can be divided into two phases: the oxidative
phase and the non-oxidative phase. In the oxidative phase, glucose-6-phosphate is
oxidized to form ribulose-5-phosphate, generating NADPH in the process. This phase is
essential for generating NADPH for biosynthetic reactions and maintaining cellular redox
balance.
The non-oxidative phase of the PPP involves a series of reversible reactions that
interconvert various pentose sugars, such as ribulose-5-phosphate, ribose-5-phosphate,
and xylulose-5-phosphate. These reactions allow cells to generate pentose sugars for
nucleotide synthesis and other biosynthetic processes without consuming glucose-6-
phosphate.
Other mutations include;
 Fructose-6-Phosphate is converted to N-acetylglycosamine which is modification
factor responsible for most cell modifications.
 Dihydroxyacetone phosphate is also a metabolite in phospholipid biosynthesis.
Phospholipid forms cell membrane influence excessive cell growth in cancer cells.
  3-Phosphoglycerate is converted to glysine and serine amino acids necessary for
cancer cell proliferation.
Note that the relationship between glycolysis & cancer is linked with other metabolic
pathways for its efficient growth i.e. TCA cycle, fatty acid synthesis, lipid synthesis.
Link with TCA (Krebs) cycle
HIF 1 is degraded by prolyl hydroxylase enzyme in sufficient oxygen. The activity of this
enzyme in highly influenced by Vitamin C availability and α-ketoglutarate from Krebs cycle.
Succinate and Fumarate compete for the active site of prolyl hydroxylase with α-
ketoglutarate; thus, cancer cells inhibit the activity of succinate dehydrogenase and
fumarase causing accumulation of succinate and fumarate. This reduces the efficiency of
prolyl hydroxylase and accumulation of HIF 1.

MicroRNA involvement
microRNA degrades genes for certain glucose transporters and enzymes thus reducing
glycolysis level in cells. Their absence leads to over expression of those glucose
transporters and enzymes.
 Breast cancer; absence of miRNA-22 which targets GLUT 1
 Ovarian cancer; absence of miRNA-144 which targets GLUT 1
 Renal (Kidney) cancer; absence of miRNA-129 which targets GLUT 1
 Bladder cancer; absence of miRNA-195-5p which targets GLUT 3
 Head, Lung, Neck, Glioma cancers; absence of miRNA-143 which targets HKII
MTOR activation downregulates microRNA.

Diagnosis of Cancer
In the diagnosis of cancer, fludeoxyglucose is used which is an isotope resembling glucose
molecule and is up taken by but not metabolized. The fludeoxyglucose quantity is then
measured by scanning with radiation as it is fluorescent. This gives a view of the way in
which glucose is being up taken by cells. High glucose uptake is a characteristic of the
cancer cells.
Therapy of Cancer
Chemotherapy works by targeting rapidly dividing cells, which are common in cancer cells.
Chemotherapy works by interfering with the cell division process, which is necessary for
cancer cells to grow and spread. Chemotherapy drugs target different phases of the cell
cycle to prevent cancer cells from dividing and replicating.
These drugs can also affect normal cells of hair follicles, bone marrow, digestive system in
the body that also divide rapidly, leading to side effects such as hair loss, nausea, fatigue,
and lowered immunity.
Drugs containing colony-stimulating factors to boost the production of white blood cells
that counteract with the chemicals are given; together with blood transfusion and anti-
nausea drugs.
In early stages, chemotherapy is supplemented with radiotherapy.
In excessive cancer, it is supplemented with stem-cell therapy.
Chemotherapy can be administered in various ways, including intravenously, orally, or
through injections. The choice of chemotherapy regimen depends on the type of cancer
being treated, the stage of the cancer, and the overall health of the patient. Some patients
may receive chemotherapy in cycles, with breaks in between to allow the body to recover
from the treatment. The duration of chemotherapy treatment can vary, ranging from a
few weeks to several months or even years.