Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability

Pui Kei Wu, Seung Keun Hong, Dmytro Starenki, Kiyoko Oshima, Hao Shao, Jason E. Gestwicki, Susan Tsai, Jong In Park

Research output: Contribution to journalArticle

Abstract

The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) is often upregulated and mislocalized in MEK/ERK-deregulated tumors. Here, we show that mortalin depletion can selectively induce death of immortalized normal fibroblasts IMR90E1A when combined with K-RasG12V expression, but not with wild-type K-Ras expression, and that K-RasG12V-driven MEK/ERK activity is necessary for this lethality. This cell death was attenuated by knockdown or inhibition of adenine nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca2+ uniporter (MCU), which implicates a mitochondria-originated death mechanism. Indeed, mortalin depletion increased mitochondrial membrane permeability and induced cell death in KRAS-mutated human pancreatic ductal adenocarcinoma (PDAC) and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21CIP1. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-RasG12V-expressing IMR90E1A and KRAS-mutated tumor cell lines in vitro. Moreover, JG-231, a JG-98 analog with improved microsomal stability effectively suppressed the xenograft of MIA PaCa-2, a K-RasG12C-expressing human PDAC line, in athymic nude mice. These data demonstrate that oncogenic KRAS activity sensitizes cells to the effects of mortalin depletion, suggesting that mortalin has potential as a selective therapeutic target for KRAS-mutated tumors.

Original languageEnglish (US)
Pages (from-to)4257-4270
Number of pages14
JournalOncogene
Volume39
Issue number21
DOIs
StatePublished - May 21 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Wu, P. K., Hong, S. K., Starenki, D., Oshima, K., Shao, H., Gestwicki, J. E., Tsai, S., & Park, J. I. (2020). Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability. Oncogene, 39(21), 4257-4270. https://doi.org/10.1038/s41388-020-1285-5