Faculty Collaboration Database

Mortalin depletion induces MEK/ERK-dependent and ANT/CypD-mediated death in vemurafenib-resistant B-Raf^V600E melanoma cells. Cancer Lett 2021 Apr 01;502:25-33

Date

01/14/2021

Pubmed ID

33440231

Pubmed Central ID

PMC7897271

DOI

10.1016/j.canlet.2020.12.044

Scopus ID

2-s2.0-85099283545 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

Therapy resistance to a selective B-Raf inhibitor (BRAFi) poses a challenge in treating patients with BRAF-mutant melanomas. Here, we report that RNA interference of mortalin (HSPA9/GRP75), a mitochondrial molecular chaperone often upregulated and mislocalized in melanoma, can effectively induce death of vemurafenib-resistant progenies of human B-Raf^V600E melanoma cell lines, A375 and Colo-829. Mortalin depletion induced death of vemurafenib-resistant cells at similar efficacy as observed in vemurafenib-naïve parental cells. This lethality was correlated with perturbed mitochondrial permeability and was attenuated by knockdown of adenine nucleotide translocase (ANT) and cyclophilin D (CypD), the key regulators of mitochondrial permeability. Chemical inhibition of MEK1/2 and ERK1/2 also suppressed mortalin depletion-induced death and mitochondrial permeability in these cells. These data suggest that mortalin and MEK/ERK regulate an ANT/CypD-associated mitochondrial death mechanism(s) in B-Raf^V600E melanoma cells and that this regulation is conserved even after these cells develop BRAFi resistance. We also show that doxycycline-induced mortalin depletion can effectively suppress the xenografts of vemurafenib-resistant A375 progeny in athymic nude mice. These findings suggest that mortalin has potential as a candidate therapeutic target for BRAFi-resistant BRAF-mutant tumors.

Author List

Wu PK, Hong SK, 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

Adenine Nucleotide Translocator 3
Animals
Cell Line, Tumor
Cyclophilins
Doxycycline
Drug Resistance, Neoplasm
Extracellular Signal-Regulated MAP Kinases
Female
Gene Knockdown Techniques
HSP70 Heat-Shock Proteins
Humans
Melanoma
Mice
Mice, Nude
Mitochondrial Proteins
Mitogen-Activated Protein Kinase Kinases
Mutation
Proto-Oncogene Proteins B-raf
Xenograft Model Antitumor Assays