1,25-Dihydroxyvitamin D 3 suppresses gastric cancer cell growth through VDR- and mutant p53-mediated induction of p21

• DOI: 10.1016/j.lfs.2017.04.021
• Publication Date: 2017-04-29T09:15:13Z
• Authors: Mingxing Li; Longfei Li; Lin Zhang; Wei Hu; Jing Shen; Zhangang Xiao; Xu Wu; Franky Leung Chan; Chi Hin Cho
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; 0301 basic medicine; Antineoplastic Agents; Cell Cycle Checkpoints; Flow Cytometry; Cell Line; 3. Good health; 03 medical and health sciences; Calcitriol; Stomach Neoplasms; Cell Line, Tumor; Mutation; Humans; Receptors, Calcitriol; RNA, Small Interfering; Tumor Suppressor Protein p53; Cell Proliferation

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.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.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.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.