CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma

Ding Ma; Shuwen Liu; Kua Liu; Qinyu He; Lili Hu; Weiwei Shi; Yin Cao; Guang Zhang; Qilei Xin; Zhongxia Wang; Junhua Wu; Chunping Jiang

Translational Oncology (Sep 2024)

CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma

Ding Ma,
Shuwen Liu,
Kua Liu,
Qinyu He,
Lili Hu,
Weiwei Shi,
Yin Cao,
Guang Zhang,
Qilei Xin,
Zhongxia Wang,
Junhua Wu,
Chunping Jiang

Affiliations

Ding Ma: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China
Shuwen Liu: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Kua Liu: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Qinyu He: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Lili Hu: Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Weiwei Shi: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Yin Cao: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Guang Zhang: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
Qilei Xin: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China
Zhongxia Wang: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Corresponding authors.
Junhua Wu: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China; Corresponding authors.
Chunping Jiang: Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China; State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Corresponding authors.

Journal volume & issue: Vol. 47
p. 102040

Abstract

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Background and Purpose: Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there is an inevitably high rate of drug resistance associated with regorafenib, which reduces its effectiveness in clinical treatment. Thus, there is an urgent need to find a potential way to solve the problem of regorafenib resistance. The metabolite of disulfiram complexed with copper, the Diethyldithiocarbamate-copper complex (CuET), has been found to be an effective anticancer drug candidate. In the present study, we aimed to evaluate the effect of CuET on regorafenib resistance in HCC and uncover the associated mechanism. Experimental Approach: Regorafenib-resistant HCC strains were constructed by applying an increasing concentration gradient. This study employed a comprehensive range of methodologies, including the cell counting kit-8 (CCK-8) assay, colony formation assay, cell cycle analysis, wound healing assay, Transwell assay, tumor xenograft model, and immunohistochemical analysis. These methods were utilized to investigate the antitumor activity of CuET, assess the combined effect of regorafenib and CuET, and elucidate the molecular mechanism underlying CuET-mediated regorafenib resistance. Key Results: The inhibitory effect of regorafenib on cell survival, proliferation and migration was decreased in regorafenib-resistant MHCC-97H (MHCC-97H/REGO) cells compared with parental cells. CuET demonstrated significant inhibitory effects on cell survival, proliferation, and migration of various HCC cell lines. CuET restored the sensitivity of MHCC-97H/REGO HCC cells to regorafenib in vitro and in vivo. Mechanistically, CuET reverses regorafenib resistance in HCC by suppressing epithelial-mesenchymal transition (EMT) through inhibition of the ERK signaling pathway. Conclusion and Implications: Taken together, the results of this study demonstrated that CuET inhibited the activation of the ERK signaling pathway, leading to the suppression of the epithelial-mesenchymal transition (EMT) and subsequently reversing regorafenib resistance in HCC both in vivo and in vitro. This study provides a new idea and potential strategy to improve the treatment of regorafenib-resistant HCC.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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