Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability

Menée in vitro et à l'aide de xénogreffes sur un modèle murin, cette étude met en évidence un mécanisme par lequel la protéine chaperon HSPA9, en supprimant la perméabilité de la membrane mitochondriale associée au translocateur adénylique mitochondrial ANT3, favorise la survie des cellules cancéreuses présentant une mutation du gène BRAF

Résumé en anglais

Oncogenic stress can kill cells, yet oncogenic mutations in the kinase BRAF result in enhanced cell survival, often despite the use of targeted inhibitors. Wu et al. found that a heat shock protein (HSP70)–related chaperone protein called mortalin was critical to blocking a cell death mechanism in BRAF-mutant cells. They found that aberrant activity of the MEK-ERK signaling cascade caused by BRAF mutation or RAF-derived fusion protein promoted a protein-protein interaction that, in the absence of mortalin, induced mitochondrial-mediated cell death. Depleting mortalin or treating cells with HSP70 inhibitor derivatives was cytotoxic selectively to BRAF-mutant cells, including those resistant to the BRAF inhibitor vemurafenib, suggesting that blocking mortalin might be therapeutically effective in BRAF-MEK-ERK pathway–driven tumors.Mortalin [also known as heat shock protein family A (HSP70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often up-regulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was selectively lethal to tumor and immortalized normal cells expressing the mutant kinase B-RafV600E or the chimeric protein ΔRaf-1:ER and that MEK-ERK–sensitive regulation of the peptide-binding domain in mortalin was critical to cell survival or death. Proteomics screening identified adenine nucleotide translocase 3 (ANT3) as a previously unknown mortalin substrate and cell survival/death effector. Mechanistically, increased MEK-ERK signaling activity and mortalin function converged opposingly on the regulation of mitochondrial permeability. Specifically, whereas MEK-ERK activity increased mitochondrial permeability by promoting the interaction between ANT3 and the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by inhibiting this interaction. Hence, mortalin depletion increased mitochondrial permeability in MEK-ERK–deregulated cells to an extent that triggered cell death. HSP70 inhibitor derivatives that effectively inhibited mortalin suppressed the proliferation of B-RafV600E tumor cells in culture and in vivo, including their B-Raf inhibitor–resistant progenies. These findings suggest that targeting mortalin has potential as a selective therapeutic strategy in B-Raf–mutant or MEK-ERK–driven tumors.