Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors

Abstract

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER–mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.

Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib‐resistant BRAFV600E mutation bearing metastatic melanoma cells

“…The hallmark of metabolic reprogramming by cancer cells has long been held to be under aerobic conditions, a shift towards glycolysis as the key energy production mechanism first observed by Dr. Otto Warburg in the mid‐twentieth century . Interestingly, a consistent trend of elevated oxidative phosphorylation and mitochondrial biogenesis has been observed in BRAF inhibitor‐resistant BRAF V600E melanomas as a consequence of the development of drug resistance . For that reason, the results of our high‐throughput screening made sense as we identified the electron transport chain inhibitors rotenone and deguelin as two of the three most potent compounds against vemurafenib‐treated BRAF V600E /PTEN‐null A2058 melanoma cells.…”

“…26 Interestingly, a consistent trend of elevated oxidative phosphorylation and mitochondrial biogenesis has been observed in BRAF inhibitor-resistant BRAF V600E melanomas as a consequence of the development of drug resistance. 27,28 For that reason, the results of our high-throughput screening made sense as we identified the electron transport chain inhibitors rotenone and deguelin 29 as two of the three most potent compounds against vemurafenib-treated BRAF V600E /PTEN-null A2058 melanoma cells.…”

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

“…66 Conversely, knockdown of the fusion-promoting protein mitofusin 2 in melanoma cells induced a more fragmented mitochondrial phenotype and increased cell death upon Vemurafenib treatment. 67 Therefore, our results might suggest that prevention or reversal of mitochondrial filamentation could be a strategy to overcome Vemurafenib resistance in BRAF V600E melanoma cells.…”

Oncogenic KRAS suppresses store-operated Ca 2+ entry and I CRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines

“…Notably, Ca 2+ interacts with the KRAS-RAF-MEK-ERK pathway at multiple levels as well as engaging overlapping downstream mediators [8–10]. For example, inhibition of BRAF increases the expression of Ca 2+ ATPase isoform 4b (PMCA4) [11] and facilitates endoplasmic reticulum (ER)mitochondrial Ca 2+ transfer [12], while opening of canonical transient receptor potential 3 (TRPC3) non-selective cation channels is required for ERK activation in B-lymphocytes [13]. Like KRAS, Ca 2+ signals have pleiotropic effects controlling cellular life and death decisions [14–16].…”