Inhibition of serum-stimulated mitogen activated protein kinase by 1α,25(OH)2-vitamin D3 in MCF-7 breast cancer cells

✍ Scribed by Daniela A. Capiati; Ana M. Rossi; Gabriela Picotto; Silvia Benassati; Ricardo L. Boland

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 378 KB
• Volume: 93
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20165

✦ Synopsis

Abstract

1α,25‐Dihydroxyvitamin D~3~ [1α,25(OH)~2~D~3~], the hormonally active form of vitamin D~3~, has been shown to be a potent negative growth regulator of breast cancer cells both in vitro and in vivo. 1α,25(OH)~2~D~3~ acts through two different mechanisms. In addition to regulating gene transcription via its specific intracellular receptor (vitamin D receptor, VDR), 1α,25(OH)~2~D~3~ induces rapid, non‐transcriptional responses involving activation of transmembrane signal transduction pathways, like growth factors and peptide hormones. The mechanisms that mediate the antiproliferative effects of 1α,25(OH)~2~D~3~ in breast cancer cells are not fully understood. Particularly, there is no information about the early non‐genomic signal transduction effectors modulated by the hormone. The present study shows that 1α,25(OH)~2~D~3~ rapidly inhibits serum induced activation of ERK‐1 and ERK‐2 MAP kinases. The tyrosine kinase Src is involved in the pathway leading to activation of ERK 1/2 by serum. Furthermore, 1α,25(OH)~2~D~3~ increases the tyrosine‐phosphorylated state of Src and inhibits its kinase activity, while induces the association of the VDR with Src, either in the presence or absence of serum. In parallel, the hormone rapidly increases the amounts of VDR associated to plasma membranes (PM). Pretreatment with the tyrosine phosphatase inhibitors orthovanadate or bpV (phen) prevented mitogen‐activated protein kinase (MAPK) inhibition by 1α,25(OH)~2~D~3~. These data altogether suggest that 1α,25(OH)~2~D~3~ inhibits the MAPK cascade by inactivating Src tyrosine kinase through a mechanism mediated by the VDR and tyrosine phosphatases. © 2004 Wiley‐Liss, Inc.