Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression
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// Balkrishna Chaube 1 , Parmanand Malvi 1 , Shivendra Vikram Singh 1 , Naoshad Mohammad 1 , Avtar Singh Meena 1,2 and Manoj Kumar Bhat 1 1 National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India 2 Current address: Department of Physiology, University of Tennessee Health Science Center, Memphis, USA Correspondence to: Manoj Kumar Bhat, email: // Keywords : melanoma; complex I; LDH; metabolic catastrophe; synthetic lethality Received : June 16, 2015 Accepted : September 23, 2015 Published : October 15, 2015 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.
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Malignant cells share a common metabolic trait, namely that they can acquire and use nutrients from a predominantly nutrient-poor environment.
“Notwithstanding the diversity of cancers, malignant cells share a common metabolic trait, namely that they can acquire and use nutrients from a predominantly nutrient-poor environment, a modus operandi that emerged as a promising target to battle tumors (202–205).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [205]
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- Authors
- Chaube, B., Malvi, P., Singh, S. V., Mohammad, N., Meena, A. S., & Bhat, M. K.
- Affiliations
- National Centre for Cell Science (IN)
- University of Tennessee Health Science Center (US)
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-10-15
- Volume
- 6
- Issue
- 35
- Pages
- 37281-37299
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4741930
- OpenAlex
- W1786422234
- Cited by
- 80
- References
- 73
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 11 · 2020: 12 · 2019: 5 · 2018: 7 · 2017: 7 · 2016: 4
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Jawaharlal Nehru University
- Council of Scientific and Industrial Research, India
- Institut National de la Santé et de la Recherche Médicale
- National Chemical Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- melanoma, mitochondrial complex I, lactate dehydrogenase, metabolic flexibility, metformin, glycolysis, oxidative phosphorylation, vascular endothelial growth factor, extracellular acidification, synthetic lethality, tumor progression, cell proliferation, apoptosis
- MeSH terms
- Lactate Dehydrogenase 5, Adenosine Triphosphate, Animals, Antineoplastic Combined Chemotherapy Protocols, Energy Metabolism, Enzyme Inhibitors, Glycolysis, Humans, Hydrogen-Ion Concentration, Isoenzymes, L-Lactate Dehydrogenase, Male, Melanoma, Melanoma, Experimental, Metformin, Mice, Inbred C57BL, Oxamic Acid, Skin Neoplasms, Time Factors, Transfection, Mice, SCID, Mice, Inbred NOD, Apoptosis, Disease Progression, Lactic Acid, Xenograft Model Antitumor Assays, RNA Interference, Vascular Endothelial Growth Factor A, Electron Transport Complex I, Cell Line, Tumor, Cell Proliferation
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