1,25-Dihydroxyvitamin D3 suppresses gastric cancer cell growth through VDR- and mutant p53-mediated induction of p21

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 Don gastric cancer was rarely studied. We aimed to investigate the antitumor effect of vitamin Don gastric cancer and underlying mechanisms. Main methods: We investigated the antitumor activity of the active form of vitamin D,1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) on gastric cancer cells (TMK1) and immortalized normal gastric cells (HFE145) by using MIT, 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)(2)D-3 by using siRNA, western blot, immunofluorescent staining and immunoprecipitation assays. Key findings: 1,25(OH)(2)D-3 could significantly inhibit proliferation and induce cell cycle arrest in TMK1 but not in HFE145. Furthermore, 1,25(OH)(2)D-3 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)(2)D-3-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)(2)D-3 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. (C) 2017 Elsevier Inc. All rights reserved.