Hyperthermia improves gemcitabine sensitivity of pancreatic cancer cells by suppressing the EFNA4/β-catenin axis and activating dCK

Qiaoxian He; Yangyang Zheng; Lei Lu; Hongzhang Shen; Weigang Gu; Jianfeng Yang; Xiaofeng Zhang; Hangbin Jin

Heliyon (Apr 2024)

Hyperthermia improves gemcitabine sensitivity of pancreatic cancer cells by suppressing the EFNA4/β-catenin axis and activating dCK

Qiaoxian He,
Yangyang Zheng,
Lei Lu,
Hongzhang Shen,
Weigang Gu,
Jianfeng Yang,
Xiaofeng Zhang,
Hangbin Jin

Affiliations

Qiaoxian He: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China
Yangyang Zheng: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China
Lei Lu: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China
Hongzhang Shen: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China
Weigang Gu: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China
Jianfeng Yang: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, 310006, Zhejiang, PR China; Hangzhou Institute of Digestive Diseases, Hangzhou, 310006, Zhejiang, PR China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, 310006, Zhejiang, PR China
Xiaofeng Zhang: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, 310006, Zhejiang, PR China; Hangzhou Institute of Digestive Diseases, Hangzhou, 310006, Zhejiang, PR China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, 310006, Zhejiang, PR China
Hangbin Jin: The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, 310006, Zhejiang, PR China; Hangzhou Institute of Digestive Diseases, Hangzhou, 310006, Zhejiang, PR China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, 310006, Zhejiang, PR China; Corresponding author. Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, PR China.

Journal volume & issue: Vol. 10, no. 7
p. e28488

Abstract

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Background: Previously, our investigations have underscored the potential of hyperthermia to improve the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC). Nonetheless, the precise underlying mechanisms remain elusive. Methods: We engineered two GEM-resistant PC cell lines (BxPC-3/GEM and PANC-1/GEM) and treated them with GEM alongside hyperthermia. The impact of hyperthermia on the therapeutic potency of GEM was ascertained through MTT assay, assessment of the concentration of its active metabolite dFdCTP, and evaluation of deoxycytidine kinase (dCK) activity. Lentivirus-mediated dCK silencing was further employed to validate its involvement in mediating the GEM-sensitizing effect of hyperthermia. The mechanism underlying hyperthermia-mediated dCK activation was explored using bioinformatics analyses. The interplay between hyperthermia and the ephrin A4 (EFNA4)/β-catenin/dCK axis was investigated, and their roles in GEM resistance was further explored via the establishment of xenograft tumor models in nude mice. Results: Hyperthermia restored dCK expression in GEM-resistant cell lines, concurrently enhancing GEM sensitivity and fostering DNA damage and cell death. These observed effects were negated by dCK silencing. Regarding the mechanism, hyperthermia activated dCK by downregulating EFNA4 expression and mitigating β-catenin activation. Overexpression of EFNA4 activated the β-catenin while suppressing dCK, thus diminishing cellular GEM sensitivity—a phenomenon remediated by the β-catenin antagonist MSAB. Consistently, in vivo, hyperthermia augmented the therapeutic efficacy of GEM on xenograft tumors through modulation of the ephrin A4/β-catenin/dCK axis. Conclusion: This study delineates the role of hyperthermia in enhancing GEM sensitivity of PC cells, primarily mediated through the suppression of the EFNA4/β-catenin axis and activation of dCK.

Published in Heliyon

ISSN: 2405-8440 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Science: Science (General); Social Sciences: Social sciences (General)
Website: https://www.cell.com/heliyon/home

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