Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability
Copyright policy )Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability
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.
- Johns Hopkins University School of Medicine United States
- Johns Hopkins Medicine United States
- UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- University of California San Francisco United States
- Johns Hopkins University United States
Proto-Oncogene Proteins p21(ras) (mesh), Permeability (mesh), Nude, Mice, Cell Death (mesh), Neoplasms, 1103 Clinical Sciences (for), Animals (mesh), 2.1 Biological and endogenous factors, Aetiology, 32 Biomedical and Clinical Sciences (for-2020), 3101 Biochemistry and cell biology (for-2020), Cancer, Cancer (rcdc), HCT116 Cells (mesh), Humans (mesh), Neoplasms (mesh), Pancreatic Cancer (rcdc), Cell Death, Mice (mesh), 1112 Oncology and Carcinogenesis (for), Biological Sciences, HSP70 Heat-Shock Proteins (mesh), Antineoplastic Agents (mesh), Mitochondrial Membranes (mesh), 5.1 Pharmaceuticals, Mitochondrial Membranes, Female, Development of treatments and therapeutic interventions, Digestive Diseases (rcdc), Nude (mesh), Oncology and Carcinogenesis, Clinical Sciences, 610, Mice, Nude, Antineoplastic Agents, Mitochondrial Proteins (mesh), Article, Permeability, Rare Diseases (rcdc), Mitochondrial Proteins, Proto-Oncogene Proteins p21(ras), Pancreatic Cancer, Rare Diseases, 5.1 Pharmaceuticals (hrcs-rac), Xenograft Model Antitumor Assays (mesh), 3211 Oncology and carcinogenesis (for-2020), Animals, Humans, HSP70 Heat-Shock Proteins, Oncology & Carcinogenesis, 31 Biological Sciences (for-2020), Biomedical and Clinical Sciences, Oncology and carcinogenesis, 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), HCT116 Cells, Xenograft Model Antitumor Assays, 3101 Biochemistry and Cell Biology (for-2020), 3211 Oncology and Carcinogenesis (for-2020), Oncology & Carcinogenesis (science-metrix), Female (mesh), Biochemistry and cell biology, Biochemistry and Cell Biology, Digestive Diseases
Proto-Oncogene Proteins p21(ras) (mesh), Permeability (mesh), Nude, Mice, Cell Death (mesh), Neoplasms, 1103 Clinical Sciences (for), Animals (mesh), 2.1 Biological and endogenous factors, Aetiology, 32 Biomedical and Clinical Sciences (for-2020), 3101 Biochemistry and cell biology (for-2020), Cancer, Cancer (rcdc), HCT116 Cells (mesh), Humans (mesh), Neoplasms (mesh), Pancreatic Cancer (rcdc), Cell Death, Mice (mesh), 1112 Oncology and Carcinogenesis (for), Biological Sciences, HSP70 Heat-Shock Proteins (mesh), Antineoplastic Agents (mesh), Mitochondrial Membranes (mesh), 5.1 Pharmaceuticals, Mitochondrial Membranes, Female, Development of treatments and therapeutic interventions, Digestive Diseases (rcdc), Nude (mesh), Oncology and Carcinogenesis, Clinical Sciences, 610, Mice, Nude, Antineoplastic Agents, Mitochondrial Proteins (mesh), Article, Permeability, Rare Diseases (rcdc), Mitochondrial Proteins, Proto-Oncogene Proteins p21(ras), Pancreatic Cancer, Rare Diseases, 5.1 Pharmaceuticals (hrcs-rac), Xenograft Model Antitumor Assays (mesh), 3211 Oncology and carcinogenesis (for-2020), Animals, Humans, HSP70 Heat-Shock Proteins, Oncology & Carcinogenesis, 31 Biological Sciences (for-2020), Biomedical and Clinical Sciences, Oncology and carcinogenesis, 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), HCT116 Cells, Xenograft Model Antitumor Assays, 3101 Biochemistry and Cell Biology (for-2020), 3211 Oncology and Carcinogenesis (for-2020), Oncology & Carcinogenesis (science-metrix), Female (mesh), Biochemistry and cell biology, Biochemistry and Cell Biology, Digestive Diseases
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