1. Deregulating Cellular Energetics
Dec 7, 2017

2. Hallmarks of Cancer, 2011

3. Food and Cancer Association
Epidemiological Studies support the role of diet in both causation and prevention of cancer

4. Food and Cancer Association
Migration studies show an increase in colorectal rates from low-risk ethnic groups after migration to high-risk locations

5. Basic Food Groups and Metabolism

6. Microconstituents
Biologically active compounds that often act as antioxidants that inhibit or delay the damaging action of ROS

7. Causative Factors of Cancer
Aspects of diet can be considered causative factors of cancer
Food is complex and can carry harmful factors in addition to nutritional value
Lack of an essential nutrient may enhance the risk of cancer
Health issues such as obesity and chronic alcohol consumption

8. Carcinogenic Contaminents
Toxins produced by molds can contaminate food and can result in forming DNA adducts and are genotoxic
Aflatoxin B from Aspergilua flavus is found on peanuts
-Produces GC to TA transversions
-Hepatocellular carcinoma
Fumonisin B is found on corn
Food preservatives like sodium nitrate are regulated
-carcinogenic N-nitroso compounds

9. Dietary Deficiencies
Micronutrient deficiencies also contribute to cancer risk
Deficiency in folate
(B vitamin) increases
the risk of colorectal
cancer
Involved with one
Carbon metabolism

10. DNA Synthesis or DNA Methylation
Methylenetetrahydrofolate reductase

11. DNA Synthesis or DNA Methylation
Foalte depletion contributes to tumor development;
-Disruption in nucleotide synthesis lead to DNA instability and potential mutation
-Disruption in methylation may cause genomic hypomethyltion

12. DNA Synthesis or DNA Methylation
Foalte depletion contributes to tumor development;
1. Disruption in nucleotide synthesis lead to DNA instability and potential mutation
-Increased incorporation of uracil into DNA and increased strand breakage due to repair mechanisms
Disruption in methylation may cause genomic hypomethylation
-Changes in epigenetic regulation
Characteristics are found in folate-deficient humans

13. Obesity and Alcohol Consumption
-15-20% of all cancer deaths in the US can be attributed to being overweight
-Increases the risk of cancers (colon, breast, endometrium, kidney, pancreas, liver, and esophagus)
-Altered sex hormone metabolism (adipocyte hormones)
-Increased insulin signaling pathways
Alcohol Consumption
-Alcohol classified as a carcinogen in 2007
-Alcohol dehydrogenase converts alcohol to acetaldehyde
-Aldehyde can bind directly to DNA forming adducts and potential mutations
-7-19% of oral cancers linked to alcohol

14. Preventative Factors
-the ability to block DNA damage caused by ROS and/or carcinogens
-Micronutrients in fruits and vegetables are beneficial
-Mediterranean diet
-Vitamin C is water soluble can scavenge for ROS
-It can be regenerated by the
enzyme Vitamin C reductase

15. Preventative Factors
-Vitamin E is lipid soluble and can scavenge for ROS
-It terminates chain reactions of free radicals in membranes

16. Microconstituents
Biologically active compounds that often act as antioxidants that inhibit or delay the damaging action of ROS

17. Regulation of Detoxification Genes
Nutrigenomics – Dietary constituents can affect the expression of certain genes
Antioxidant response element (ARE)
-5’ – A/G TGA C/T NNNGC A/G – 3’ in the promoter region
-encode detoxification and antioxidant enzymese
-reacts to sulforaphane (vegatables), epigallo-catechin-3- gallate (EGCG, Green tea), reactive electrophilic intermediates H2O2 (carcinogens)

18. Regulation of Detoxification Genes
Kelch-like ECH-associated protein 1 (Keap1)
Nuclear factor E2-related factor 2 (Nrf2)

19. Regulation of Detoxification Genes

20. Regulation of Detoxification Genes

21. Keap1-Nrf2 Pathway
Elevated levels of Nrf2 in cancer cells may protect them from chemotherapeutic agents during treatment

22. Warburg Effect
-In tumor cells, high level of glycolysis even in the presence of Oxygen
-Aerobic glycolysis, Warburg Effect
-Much less energy is being produced 2 ATP per glucose instead of 36 ATP
-Glycolytic intermediates could meet biosynthetic needs of proliferating tumor cells

23. Warburg Effect

24. Regulators of Glycolysis in Tumors

25. Glycolysis Pathway
Transport of Glucose into the cell

26. HIF-1α -Direct transctivation of glucose Transporters (GLUTs)
-Activation of glycolytic enzymes of hexokinase II (1st step)
-Activation pyruvate dehydrogenase I which phosphorylates pyruvate not allowing it to enter the TCA cycle
-Increased levels of PKM1, resulting in accumulation of metabolites for biosynthesis

27. HIF-1α

28. PI3K-Akt—mTOR Pathway
A tyrosine kinase receptor (EGFR, PDGFR) can activated PI3K and then Akt can be activated
-Akt activates mTOR signaling and activates transcription factors

29. PI3K-Akt—mTOR Pathway -Glycolysis upregulation involves: -HKII -PFK2
-GLUT1, Glucose Transporter
Glycolytic
Enzyme

30. PI3K-Akt—mTOR Pathway

31. K-Ras Activation of K-Ras (G12V) causes mitochondrial dysfunction
K-Ras leads to increased expression of GLUT1
K-Ras mutated cells show increased survival in low glucose culture conditions

32. p53
p53 promotes oxidative phosphorylation and inhibits glycolysis in several ways;
Inhibits GLUTS
Inhibits Glycolytic enzymes
Activation of Inhibitors of Glycolysis
Negatively regulates PI3K-Akt-mTOR pathway
Therefore: p53 is typically mutated

33. miRNAs
Accumulating evidence that miRNAs are helping to induce aerobic glycolysis