Bioenergetics of Cancer

1. ROLE OF MITOCHONDRIAL AND
HEME FUNCTION IN LUNG CANCER
BIOENERGETICS AND
TUMORIGENESIS

2. LUNG CANCER AND NSCLC
• Most common cause of cancer deaths worldwide.
• 85% have NSCLC- A subtype which is further classified in 2 subtypes.
• Lung adenocarcinoma (LUAD)
• Lung squamous cell carcinoma (LUSC)
• Most common reason is Smoking
• Eradication of tobacco related products is the key component in fight against NSCLC.

3. METABOLIC PATHWAYS IN A CELL
• Cells require ATP and other energy currencies to carry out various processes
• ATP synthesis occurs through many pathways with different substrates.
• Glucose being the primary substrate.
• Glycolytic pathway and Oxidative phosphorylation are two main pathways involved.
• Glycolytic pathway yields lactate gives out less ATP as compared to Oxidative
Phosphorylation which yields out CO2 and H20.

5. ALTERNATIVE SUBSTRATES FOR CELL.
• Under certain conditions, cells can rely on other substrates, besides glucose to carry out
their metabolic processes and fetch energy from them.
• Glutamine, an amino acid, can be used as in glutaminolysis.
• Lactate, a by product of fermentation can be utilized back in OXPHOS, via reconversion
into pyruvate.
• Fatty acids, Ketone bodies can be incorporated in Krebs’ cycle via conversion into
Acetyl-CoA.

7. GENETIC AND PROTEMIC DIFFERENCES IN
NORMAL AND NSCLC CELLS
• B-Raf (BRAF), kirsten rat sarcoma viral oncogene (KRAS), anaplastic lymphoma kinase
(ALK), and epidermal growth factor receptor (EGFR) are the targets of driver mutations.
• Insensitivity to GTPase activating proteins is caused by activating mutations in Ras
guanosine nucleotide-binding proteins leading to increased TCA cycle activity.
• IDH1, IDH2 genes are disturbed.
• ATP synthase enzymes is expressed much higher than normal cells.
• ME and ACLY enzymes are expressed, Akt phosphorylates the ACLY leading to
increased production.

8. ROLE OF HEME IN LUNG CANCER
• Importance of Heme
as a prosthetic group for various important biological components such as hemoglobin,
myoglobin and also in mitochondrial respiratory complexes
biological processes such as pancreatic development
Cellular processes such as cell cycle, transcription and translation
Abnormal levels of heme ?

9. EXPERIMENTS CONDUCTED FOR FINDING
HEME’S RELATION WITH LUNG CANCER
• Heme, a dietary component
• Red-meat, a heme rich dietary component
• Experiment results: 24% increased risk of Cancer
• Heme levels in Cell lines of NSCLC were compared to those of normal cells

10. EXPERIMENTS CONDUCTED FOR FINDING
HEME’S RELATION WITH LUNG CANCER
• ALAS1 (5-aminolevulic acid synthase)
• Inhibition of ALAS1 lead to inhibition of cancer cell proliferation
• Heme also acts as cofactor for proteins involved in oxygen transport or oxygen
utilization and in electron transport chain.

12. MORE HEME > MORE OXPHOS > MORE
CARCINOGENESIS

13. ROLE OF MITOCHONDRIAL MUTATIONS
AND COPY NUMBER IN LUNG CANCER
• Mitochondrial DNA; more prone to mutations due to lack of safeguards like introns and histones
• Also, no DNA-repair machineries present in its nucleus
• So, prone to mutations when exposed to ROS
• Results in change in copy number and mutations
• To avoid the mutations, mitochondria increase their copy number.

14. RELATION OF LUNG ADENOCARCINOMA TO
COPY NUMBER
• In case of Lung carcinoma, carcinogenesis associated with copy number
• The association was directly proportional
• NOT A UNIVERSAL RULE.

15. TFAM
• A transcription factor, that binds to mitochondrial DNA
• This results in higher gene expression of mitochondria
• So, this protein is also linked to more copy number and ultimately more carcinogenesis

16. OTHER GENES OF MITOCHONDRIAL
BIOGENESIS INVOLVED IN CANCER
• Various genes involved in mitochondrial biogenesis are also directly proportional to the
metastatic potential
• For example, PGC-1α
• Increases oxygen consumption, mitochondrial biogenesis, OXPHOS and ultimately fuels
metastases

17. RELATION OF MITOCHONDRIAL INHIBITION
TO TUMOR PROGRESSION INHIBITION
• Oxidative phosphorylation is crucial for anchorage-independent cancer cell proliferation
• Suppression of OXPHOS > Suppression of tumorigenic capacity of cancer cells
• So if mitochondria is targeted or inhibited
no OXPHOS
no ATP
Limited growth of tumors

18. RELATION OF MITOCHONDRIAL INHIBITION
TO TUMOR PROGRESSION INHIBITION
• Studies showed high levels of oxygen in NSCLC cell lines as compared to normal cells
• When mitochondria are targeted, cancer cells become more susceptible to cytotoxic
drugs

19. CYCLOPAMINE
• What is cyclopamine?! > An inhibitor in various signaling pathways
• It has certain anti-carcinogenic properties
• Generates ROS, which disturb tumor cell mitochondria
• Can also induce mitochondrial fission in various cancer cell lines
• Hence, no tumor.

20. METFORMIN
• What is metformin? >A drug used to alleviate diabetes type II
• Anti-cancer properties in mammals
• Patients taking metformin> lesser cancer risks
• Reduces oxygen consumption in the presence of pyruvate
• As a result, mitochondrial complex 1 gets starved of NADH
• So, lesser OXPHOS and as a result lesser cancer
• THIS IS ALSO NOT UNIVERSAL> Some Healthy cells don’t get affected by
mitochondrial inhibitors

21. ROLE OF MICROENVIRONMENT IN THE
PROLIFERATION OF CANCER CELL
• When Mitochondria face substantial challenges, the tumor microenvironment acts as an
alternative source for cancer cells proliferation
• Stromal cells in the microenvironment supply the cells with lactate that acts as an
energy source
• So, these fibroblasts and pericytes provide the cells with metabolites that fuel the cancer
cells
• Blood vessels are also the components of microenvironment and aid in the process

23. MITOCHONDRIA AND OXPHOS PLAY
A KEY ROLE IN DRUG RESISTANCE

24. DRUG RESISTANCE
• Drug resistance is one of the major hurdles of an effective cancer therapy. Some
populations of the cells remain dormant during therapy and subsequently become
resistant.
• The resistant cells continue to establish their clonal populations, metastasis, and result
in poor survival outcomes.
• Therefore, to solve drug resistance is very vital to improve the treatment outcome.

25. MITOCHONDRIA AND OXPHOS
• Mitochondria have long been associated with ATP generation and ROS production in
cancer.
• Recent studies have shown that several cancers have adapted their cells to rely more
on mitochondrial OXPHOS.
• Cancer cells have shifted gears to elevated OXPHOS through several different
mechanisms ranging from gene upregulations to abnormal protein expressions

27. • Fig. 2. Apoptosis-resistant mitochondria and cancer.
• Resistance to mitochondrial membrane permeabilization (MMP) is a common
phenomenon observed in cancer cells. It often arises from blocking the permeability
transition pore complex (PTPC) opening or due to the failure of pro-apoptotic BAX
activation by anti-apoptotic BCL-2 family members. As a result, the release of pro-
apoptotic proteins from the mitochondrial intermembrane space is inhibited.
• Resistance also arises from the down regulation of pro-apoptotic factors (proteins
or second messengers such as calcium) and up-regulation of anti-apoptotic proteins,
thus tilting the balance toward survival.

28. • NSCLC cells that are resistant to EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) were shown to
exhibit elevated OXPHOS accompanied by elevated glycolysis and activity in TCA cycle.
• This metabolic shift to increased OXPHOS was found to be a result of MET (mesenchymal–epithelial
transition factor) proto-oncogene expression in the mitochondrial membrane in addition to plasma
membrane.
• Pharmacological inhibition of MET resulted in cytotoxicity and apoptosis.
• Interestingly, cancer cells rewire metabolism by altering the localization of proteins and expressing them
ectopically in mitochondria.
• 3-Oxoacid CoA-transferase 1 (OXAT1) and acetyl-CoA acetyltransferase 1 (ACAT1) are proteins
localized in mitochondria and are involved in utilization of ketone bodies to aid in tumor growth and
metastasis.

29. • A recent study showed that cisplatin-resistant lung adenocarcinoma cells exhibit higher
resistence to mitochondrial membrane potential (MMP) and intracellular ATP levels than
the non-resistant cells which confer migratory and invasive abilities to these cells.
Inhibition of mitochondrial complex I abolished the ability of the resistant cells to invade,
suggesting the pivotal role of mitochondria in metastasis of resistant cells.

30. THANKYOU 