Faculty Collaboration Database

Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability. Oncogene 2020 May;39(21):4257-4270

Date

04/16/2020

Pubmed ID

32291414

Pubmed Central ID

PMC7244387

DOI

10.1038/s41388-020-1285-5

Scopus ID

2-s2.0-85083767959 (requires institutional sign-in at Scopus site)   18 Citations

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-Ras^G12V expression, but not with wild-type K-Ras expression, and that K-Ras^G12V-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 p21^CIP1. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-Ras^G12V-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-Ras^G12C-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.

Author List

Wu PK, Hong SK, Starenki D, Oshima K, Shao H, Gestwicki JE, Tsai S, Park JI

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Cell Death
Female
HCT116 Cells
HSP70 Heat-Shock Proteins
Humans
Mice
Mice, Nude
Mitochondrial Membranes
Mitochondrial Proteins
Neoplasms
Permeability
Proto-Oncogene Proteins p21(ras)
Xenograft Model Antitumor Assays