Open AccessHeat shock protein 47 confers chemoresistance on pancreatic cancer cells by interacting with calreticulin and IRE1α
Author(s) -
Yoneda Akihiro,
Minomi Kenjiro,
Tamura Yasuaki
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14976
Subject(s) - calreticulin , endoplasmic reticulum , gemcitabine , cancer research , heat shock protein , intracellular , pancreatic cancer , cancer cell , apoptosis , biology , cancer , microbiology and biotechnology , chemistry , medicine , biochemistry , gene
Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemoresistant cancers. An understanding of the molecular mechanism by which PDAC cells have a high chemoresistant potential is important for improvement of the poor prognosis of patients with PDAC. Here we show for the first time that disruption of heat shock protein 47 (HSP47) enhances the efficacy of the therapeutic agent gemcitabine for PDAC cells and that the efficacy is suppressed by reconstituting HSP47 expression. HSP47 interacts with calreticulin (CALR) and the unfolded protein response transducer IRE1α in PDAC cells. Ablation of HSP47 promotes both the interaction of CALR with sarcoplasmic/endoplasmic reticulum Ca 2+ ‐ATPase 2 and interaction of IRE1α with inositol 1,4,5‐triphosphate receptor, which generates a condition in which an increase in intracellular Ca 2+ level is prone to be induced by oxidative stimuli. Disruption of HSP47 enhances NADPH oxidase‐induced generation of intracellular reactive oxygen species (ROS) and subsequent increase in intracellular Ca 2+ level in PDAC cells after treatment with gemcitabine, resulting in the death of PDAC cells by activation of the Ca 2+ /caspases axis. Ablation of HSP47 promotes gemcitabine‐induced suppression of tumor growth in PDAC cell‐bearing mice. Overall, these results indicated that HSP47 confers chemoresistance on PDAC cells and suggested that disruption of HSP47 may improve the efficacy of chemotherapy for patients with PDAC.