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Chaube , B. and Malvi , P. and Singh , S.V. and Mohammad , N. and Meena, A.S. and Bhat , M.K. (2015) Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression. Oncotarget. 2015 Nov 10;6(35):37281-99, 6 (35). pp. 37281-37299.
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58.Dr. Bhat (Oncotarget) paid open access.pdf Download (15Mb) | Preview |
Abstract
Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma.
| Item Type: | Article |
|---|---|
| Additional Information: | This is Open Access Article for full text click on web link |
| Subjects: | Cancer Biology |
| Depositing User: | Mr. Rameshwar Nema |
| Date Deposited: | 04 Dec 2015 09:11 |
| Last Modified: | 19 Feb 2016 06:01 |
| URI: | http://nccs.sciencecentral.in/id/eprint/211 |
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