Corynoline inhibits esophageal squamous cell carcinoma growth via targeting Pim-3

Yunshu Shi; Qiang Yuan; Yingying Chen; Xiaoyu Li; Yujuan Zhou; Hao Zhou; Feng Peng; Yanan Jiang; Yan Qiao; Jimin Zhao; Chi Zhang; Junyong Wang; Kangdong Liu; Zigang Dong

doi:10.1016/j.phymed.2023.155235

Corynoline inhibits esophageal squamous cell carcinoma growth via targeting Pim-3

Phytomedicine. 2024 Jan:123:155235. doi: 10.1016/j.phymed.2023.155235. Epub 2023 Dec 12.

Authors

Yunshu Shi¹, Qiang Yuan¹, Yingying Chen², Xiaoyu Li², Yujuan Zhou², Hao Zhou², Feng Peng², Yanan Jiang³, Yan Qiao², Jimin Zhao⁴, Chi Zhang⁵, Junyong Wang⁶, Kangdong Liu⁷, Zigang Dong⁸

Affiliations

¹ The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan 450052, China.
² The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China.
³ The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan 450052, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan 450000, China; Center for Basic Medical Research, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China.
⁴ The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan 450000, China; Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan 450000, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan 450000, China.
⁵ Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China.
⁶ Center for Basic Medical Research, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: wangjunyong@zzu.edu.cn.
⁷ The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan 450052, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan 450000, China; Center for Basic Medical Research, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China; Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan 450000, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan 450000, China. Electronic address: kdliu@zzu.edu.cn.
⁸ The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan 450052, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan 450000, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan 450000, China. Electronic address: dongzg@zzu.edu.cn.

PMID: 38128397
DOI: 10.1016/j.phymed.2023.155235

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival rate. Finding novel therapeutic targets and their inhibitors for ESCC prevention and therapy is urgently needed.

Methods: We investigated the proviral integration site for maloney murine leukemia virus 3 (Pim-3) protein levels using immunohistochemistry. Using Methyl Thiazolyl Tetrazolium and clone formation assay, we verified the function of Pim-3 in cell proliferation. The binding and inhibition of Pim-3 by corynoline were verified by computer docking, pull-down assay, cellular thermal shift assay, and kinase assay. Cell proliferation, Western blot, and a patient-derived xenograft tumor model were performed to elucidate the mechanism of corynoline inhibiting ESCC growth.

Results: Pim-3 was highly expressed in ESCC and played an oncogenic role. The augmentation of Pim-3 enhanced cell proliferation and tumor development by phosphorylating mitogen-activated protein kinase 1 (MAPK1) at T185 and Y187. The deletion of Pim-3 induced apoptosis with upregulated cleaved caspase-9 and lower Bcl2 associated agonist of cell death (BAD) phosphorylation at S112. Additionally, binding assays demonstrated corynoline directly bound with Pim-3, inhibiting its activity, and suppressing ESCC growth.

Conclusions: Our findings suggest that Pim-3 promotes ESCC progression. Corynoline inhibits ESCC progression through targeting Pim-3.

Keywords: Apoptosis; Corynoline; Esophageal squamous cell carcinoma; Proliferation; Proviral integration site for maloney murine leukemia virus 3.

MeSH terms

Animals
Apoptosis
Berberine Alkaloids*
Cell Line, Tumor
Cell Movement
Cell Proliferation
Esophageal Neoplasms* / drug therapy
Esophageal Neoplasms* / metabolism
Esophageal Squamous Cell Carcinoma* / drug therapy
Esophageal Squamous Cell Carcinoma* / pathology
Gene Expression Regulation, Neoplastic
Humans
Mice

Substances

corynoline
Berberine Alkaloids