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Heat shock protein 47 confers chemoresistance on pancreatic cancer cells by interacting with calreticulin and IRE1 alpha

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Title: Heat shock protein 47 confers chemoresistance on pancreatic cancer cells by interacting with calreticulin and IRE1 alpha
Authors: Yoneda, Akihiro Browse this author →KAKEN DB
Minomi, Kenjiro Browse this author
Tamura, Yasuaki Browse this author →KAKEN DB
Keywords: calreticulin
IRE1 alpha
Issue Date: 2-Jul-2021
Publisher: John Wiley & Sons
Journal Title: Cancer science
Volume: 112
Issue: 7
Start Page: 2803
End Page: 2820
Publisher DOI: 10.1111/cas.14976
Abstract: 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 IRE1 alpha in PDAC cells. Ablation of HSP47 promotes both the interaction of CALR with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 and interaction of IRE1 alpha with inositol 1,4,5-triphosphate receptor, which generates a condition in which an increase in intracellular Ca2+ 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 Ca2+ level in PDAC cells after treatment with gemcitabine, resulting in the death of PDAC cells by activation of the Ca2+/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.
Type: article
Appears in Collections:産学・地域協働推進機構 (Institute for the Promotion of Business-Regional Collaboration) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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