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

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 Ca 2+ 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.

Identification and Validation of a Proliferation-Associated Score Model Predicting Survival in Lung Adenocarcinomas

“…The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) was often upregulated in MEK/ERK-deregulated tumors [48]. Wu et al [49] demonstrated that the depletion effect of HSPA9 was sensitized by KRAS activity, suggesting that HSPA9 was a potential target for KRAS-mutated tumors.…”

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

“…Many different aspects of mitochondrial biology directly influence tumorigenesis, including alterations to cell death pathways, mitochondrial dynamics, mitochondrial biogenesis and mTOR signalling, and oxidative stress [10]. A significant number of components of the mitochondrial import machineries are overexpressed in a variety of different cancers, including subunits of the TOM complex (Tom20, Tom40, Tom7 and Tom70) [186,[188][189][190][191][192], the TIM23 complex (Tim17a, Mortalin, Magmas, Tim50 and Tim23) [186,[193][194][195][196][197][198][199][200][201][202][203][204][205][206][207], the TIM22 complex (Tim22, AGK) [186,[208][209][210][211][212][213][214][215][216][217], the small Tim chaperones (Tim8a, Tim8b, Tim9, Tim13) [186,[218][219][220] and Mia40 [221,222]. In addition, two variants of Tim44 (C925A and G1274A) have been identified in oncocytic thyroid carcinomas [223].…”

Iron–Sulfur Cluster Biogenesis as a Critical Target in Cancer

“…TNMplot analysis reveals overexpression of several proteins involved in [4Fe-4S] trafficking from the mitochondria and to the cytosol and nucleus ( Table 2 ). The NEET family of proteins (CISD1/2) at the beginning of the CIA pathway is thought to be a novel cancer target [ 112 ]. CISD2 overexpression in murine xenograft breast cancer tumors resulted in increases in tumor size, aggressiveness, and the tolerance of cells to oxidative stress [ 113 ].…”