2. Cancer in all of its forms) is the second leading cause of death in the US. O
ID: 253567 • Letter: 2
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2. Cancer in all of its forms) is the second leading cause of death in the US. One type of treatment for many tumors is the use of cytotoxic chemotherapeutic agents; the compounds used generally exhibit serious side effects due to their systemic toxicity. Currently, much of cancer research is focused on attempting to understand the altered processes that occur in cancer cells. a. What is the Warburg effect? b. What is PKM2? Why might PKM2 expression increase the ability of cancer cells to proliferate? c. Why is NADPH important in cancer cells? (Hint: there are several reasons.) How does PKM2 expression alter NADPH? Why is this true? d. How are isocitrate dehydrogenase mutations suspected to alter the functionality of cancer cells?Explanation / Answer
Answer a. The Warburg effect is the phenomenon that occurs in cancer cells in which they produce additional energy through increased oxygen-dependent glycolysis which is followed by lactic acid fermentation even in the presence of abundant oxygen. Although this process is less efficient than oxidative phosphorylation in terms of ATP production but it results in increased production of other metabolites that boost the growth of proliferating cells.
Answer b. PKM 2 is Pyruvate kinase muscle isozyme M2. It is a limiting glycolytic enzyme that catalyzes the final step in glycolysis that plays a key role in tumor metabolism and growth. PKM2 is expressed in tissues with anabolic functions, such as proliferating cells and cancer cells. In cancer cells PKM2 is overexpressed and it is controlled by a oncoprotein known as c-myc. PKM2 exists in cells in two states. Dimeric and tetrameric. Tetrameric form is highly catalytic in nature and associated with ATP synthesis and catabolic metabolism in cells. PKM2 translocation to nucleus in cancer cells is seen that results in the binding with HIF-1 alpha protein and transactivation of HIF-1 target genes. HIF 1 is a gene that regulates angiogenesis in cancer cells. Thus it can be said that PKM 2 expression can increase the ability of cancer cells to proliferate and also metastasize.
Answer c. Highly proliferating cancer cells continues to demand nucleotides and other materials for biosynthesis. NAPDH and pentose phosphate are essential fornucleotide synthesis, therefore, pentose phosphate pathway is important and frequently upregulated in many types of tumors. NADPH is also a key factor for tumor cells to defend themselves against oxidative stress, chemotherapy induced cytotoxic effect and as well as for promoting biosynthesis.
Dimeric form of PKM 2 facilitates the production of glycolytic intermediates to enter the glycolysis branch pathways, including glycerol synthesis and the pentose phosphate pathway, which produces NADPH. High expression of PKM2 leads to high production of NADPH.
Answer d. Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in brain tumors such as gliomas. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a metabolite that is utilized by cancer cells. IDH mutant cancer cells that produce 2HG, can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Mutant IDH1 and 2 also contribute to overproduction of NADPH which is a important enzyme in cancer cells that help in reduction of oxidative stress.
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