Deregulating Cellular Energetics Dec 7, 2017

Hallmarks of Cancer, 2011

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

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

Basic Food Groups and Metabolism

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

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

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

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

DNA Synthesis or DNA Methylation Methylenetetrahydrofolate reductase

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

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

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

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

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

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

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)

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

Regulation of Detoxification Genes

Regulation of Detoxification Genes

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

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

Warburg Effect

Regulators of Glycolysis in Tumors

Glycolysis Pathway Transport of Glucose into the cell

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

HIF-1α

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

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

PI3K-Akt—mTOR Pathway

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

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

miRNAs Accumulating evidence that miRNAs are helping to induce aerobic glycolysis