Mingxing Li1, Longfei Li2, Lin Zhang3, Wei Hu4, Jing Shen2, Zhangang Xiao2, Xu Wu2, Franky Leung Chan4, Chi Hin Cho5. 1. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan Province, China; School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China. Electronic address: starlee@swmu.edu.cn. 2. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan Province, China. 3. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan Province, China; School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China. 4. School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China. 5. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan Province, China; School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China. Electronic address: chcho@cuhk.edu.hk.
Abstract
AIMS: Previous studies have indicated that vitamin D deficiency correlates with cancer risk and vitamin D potentiates antitumor effects in a variety of cancers. The antitumor effect of vitamin D on gastric cancer was rarely studied. We aimed to investigate the antitumor effect of vitamin D on gastric cancer and underlying mechanisms. MAIN METHODS: We investigated the antitumor activity of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on gastric cancer cells (TMK1) and immortalized normal gastric cells (HFE145) by using MTT, colony formation and Flow cytometry assays. We demonstrated the important role of vitamin D receptor (VDR) and mutant p53 (mutp53) in mediating the antitumor action of 1,25(OH)2D3 by using siRNA, western-blot, immunofluorescent staining and immunoprecipitation assays. KEY FINDINGS: 1,25(OH)2D3 could significantly inhibit proliferation and induce cell cycle arrest in TMK1 but not in HFE145. Furthermore, 1,25(OH)2D3 stimulated p21 expression and suppressed cyclin-dependent kinase 2 (CDK2) expression in TMK1 in a VDR-dependent manner. High levels of VDR in human gastric cancer tissues and cancer cell lines implicated that vitamin D could display more potent pharmacological action against malignant cells. Besides, mutp53 but not wild type p53 was essential for 1,25(OH)2D3-stimulated upregulation of p21 in gastric cancer cells. Indeed, mutp53 could stabilize nuclear VDR level through interaction with VDR. SIGNIFICANCE: Our results suggest that 1,25(OH)2D3 inhibits gastric cancer cell growth through VDR and mutp53 interaction followed by the modulation of p21/CDK2. We propose that vitamin D might be used for the prophylactic treatment for malignant diseases in the stomach.
AIMS: Previous studies have indicated that vitamin D deficiency correlates with cancer risk and vitamin D potentiates antitumor effects in a variety of cancers. The antitumor effect of vitamin D on gastric cancer was rarely studied. We aimed to investigate the antitumor effect of vitamin D on gastric cancer and underlying mechanisms. MAIN METHODS: We investigated the antitumor activity of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on gastric cancer cells (TMK1) and immortalized normal gastric cells (HFE145) by using MTT, colony formation and Flow cytometry assays. We demonstrated the important role of vitamin D receptor (VDR) and mutant p53 (mutp53) in mediating the antitumor action of 1,25(OH)2D3 by using siRNA, western-blot, immunofluorescent staining and immunoprecipitation assays. KEY FINDINGS:1,25(OH)2D3 could significantly inhibit proliferation and induce cell cycle arrest in TMK1 but not in HFE145. Furthermore, 1,25(OH)2D3 stimulated p21 expression and suppressed cyclin-dependent kinase 2 (CDK2) expression in TMK1 in a VDR-dependent manner. High levels of VDR in humangastric cancer tissues and cancer cell lines implicated that vitamin D could display more potent pharmacological action against malignant cells. Besides, mutp53 but not wild type p53 was essential for 1,25(OH)2D3-stimulated upregulation of p21 in gastric cancer cells. Indeed, mutp53 could stabilize nuclear VDR level through interaction with VDR. SIGNIFICANCE: Our results suggest that 1,25(OH)2D3 inhibits gastric cancer cell growth through VDR and mutp53 interaction followed by the modulation of p21/CDK2. We propose that vitamin D might be used for the prophylactic treatment for malignant diseases in the stomach.
Authors: Wei Hu; Lin Zhang; Ming Xing Li; Jing Shen; Xiao Dong Liu; Zhan Gang Xiao; Ding Lan Wu; Idy H T Ho; Justin C Y Wu; Cynthia K Y Cheung; Yu Chen Zhang; Alaster H Y Lau; Hassan Ashktorab; Duane T Smoot; Evandro F Fang; Matthew T V Chan; Tony Gin; Wei Gong; William K K Wu; Chi Hin Cho Journal: Autophagy Date: 2019-01-06 Impact factor: 16.016
Authors: Swathi Ramakrishnan; Susan E Steck; Lenore Arab; Hongmei Zhang; Jeannette T Bensen; Elizabeth T H Fontham; Candace S Johnson; James L Mohler; Gary J Smith; L Joseph Su; Anna Woloszynska Journal: Prostate Date: 2019-05-11 Impact factor: 4.012
Authors: Nancy Palechor-Ceron; Ewa Krawczyk; Aleksandra Dakic; Vera Simic; Hang Yuan; Jan Blancato; Weisheng Wang; Fleesie Hubbard; Yun-Ling Zheng; Hancai Dan; Scott Strome; Kevin Cullen; Bruce Davidson; John F Deeken; Sujata Choudhury; Peter H Ahn; Seema Agarwal; Xuexun Zhou; Richard Schlegel; Priscilla A Furth; Chong-Xian Pan; Xuefeng Liu Journal: Cells Date: 2019-10-27 Impact factor: 7.666