Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression.
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.
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
Balkrishna
B
Chaube
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
Parmanand
P
Malvi
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
Shivendra Vikram
SV
Singh
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
Naoshad
N
Mohammad
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.|Current address: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
Avtar Singh
AS
Meena
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
Manoj Kumar
MK
Bhat
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010072:Oxamic Acid / Q000494:pharmacology*; D034622:RNA Interference; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D008687:Metformin; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D042967:Electron Transport Complex I; D010072:Oxamic Acid
LDH; complex I; melanoma; metabolic catastrophe; synthetic lethality