MCW Researchers Publish Mortalin/HSPA9 Targeting Study in Oncogene
The mitochondrial HSP70 chaperone mortalin is often upregulated and mislocalized in MEK/ERK-deregulated tumors. In this study, Dr. Jong-In Park’s lab in the Department of Biochemistry shows that mortalin is upregulated in human pancreatic ductal adenocarcinoma (PDAC) and its depletion or inhibition suppresses PDAC cells in vitro and in mouse xenografts. Notably, K-RasG12V-driven MEK/ERK activity is necessary for this lethality. Mechanistically, 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 PDAC and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21CIP1. 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.