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

Abstract

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.

• Authors: Pui-Kei Wu, Seung-Keun Hong, Wenjing Chen, Andrew E Becker, Rebekah L Gundry, Chien-Wei Lin, Hao Shao, Jason E Gestwicki, Jong-In Park
• Journal: Science signaling (Sci Signal) Vol. 13 Issue 622 (03 10 2020) ISSN: 1937-9145 [Electronic] United States
• PMID: 32156782 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Adenine Nucleotide Translocator 3
• HSP70 Heat-Shock Proteins
• HSPA9 protein, human
• Mitochondrial Proteins
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Adenine Nucleotide Translocator 3 (genetics, metabolism)
• Cell Line, Tumor
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Mitochondria (genetics, metabolism)
• Mitochondrial Membranes (metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Mutation
• Neoplasms (genetics, metabolism)
• Permeability
• Proto-Oncogene Proteins B-raf (genetics, metabolism)