| Summary: | 碩士 === 國立中興大學 === 生命科學系所 === 103 === There are three isoforms in malic enzymes (MEs) family which include ME1, ME2 and ME3. Mitochondrial NAD(P)+-dependent malic enzyme (ME2) is particularly expressed in tumor mitochondria and rather than normal cells . ME2 catalyzes substrate malate to generate pyruvate and accompanies with the production of NAD(P)H. In addition, ME2 participates in tumor cell metabolism pathway, glutaminolysis, which utilizes glutamine to replenish and substitute for glucose as energy source. A reciprocal negative feedback loop between tumor suppressor p53 and ME2 involves the p53-dependent cellular senescence and ME2-mediated metabolic rewiring. These observations suggest that ME2 is involved in tumor development. In addition, SIRT1 is a histone deacetylase (HDAC). Histone deacetylation may downregulate gene transcription and protein expression. SIRT1 is also found to acetylate the non-histone protein. The tumor suppressor p53 is the first discovered deacetylated non-histone protein by SIRT1. p53 is downregulated by SIRT1 deacetylation and then inactivated. Deacetylation of p53 by SIRT1 declined p53 activity and inhibited p53-dependent apoptosis, suggesting that SIRT1 activation may promote tumor survival and progression. Moreover, significant senescence-inflammatory response (SIR) may occur in cancer patients especially after chemotherapy. SIR might switch cancer development from inhibition to promotion and p53 highlighted a critical role in inhibiting SIR and tumor progression. However, p53 mutant is a frequently event in tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs) might prohibit SIR and the development of cancer. Cyclooxygenase-2 (COX-2) overexpression is found in many malignancies. Besides, multiple pro-carcinogenic roles for COX-2 has been completed from promoting tumors proliferation to chemotherapy resistance. Herein, the ME2 and SIRT1 inhibitors will be combined with chemotherapeutic agent VP16 and COX-2 inhibitor which are a prominent chemotherapeutic policy depending on p53 expression condition. Expectantly, the strategy will enhance the susceptibility of cancer drug in tumor chemotherapy.
|
|---|
