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Vitamin D‐induced anti‐cancer effects are blunted in Ki‐RAS transformed human prostate epithelial cells
Author(s) -
Zhang Zhentao,
Kovalenko Pavlo,
Li Jia,
Teegarden Dorothy,
Fleet James C.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a62-a
Subject(s) - mapk/erk pathway , calcitriol receptor , phosphorylation , activator (genetics) , cancer research , oncogene , microbiology and biotechnology , transcription factor , chemistry , mutant , biology , medicine , endocrinology , gene , biochemistry , vitamin d and neurology , cell cycle
1α, 25 dihydroxyvitamin D 3 (1,25 D) exerts anti‐cancer actions on prostate epithelial cells (PEC) but this may be blunted by common molecular changes associated with cancer. We found that 1,25 D‐induced growth arrest and gene expression were significantly diminished in Ki‐RAS oncogene transformed human PEC (RWPE2) compared to the non‐transformed parental line RWPE1. RWPE2 cells have higher levels of activated ERK1/2 (MAPK family members) than RWPE1; MAPK activation decreased 1,25 D‐induced transcriptional activity in RWPE1 while MAPK inhibitors restored it in RWPE2. This shows that enhanced MAPK activity is a mediator of the Ki‐RAS induced inhibition of 1,25 D action. In keratinocytes MAPK mediated phosphorylation of RXRα at serine 260 (S260) impairs 1,25 D action but a S260A RXRα mutant did not restore vitamin D action in RWPE2. In contrast, S32A, T82A, and Y249A mutants increased 1,25 D‐mediated gene transcription in RWPE2. Mammalian two‐hybrid assays showed that in RWPE2 the interaction between the co‐activator SRC‐1 and the RXRα ligand binding domain or the RXRα AF1 domain was reduced (by 35% and 40% respectively). Mutation of S32A and T82A in the RXRα AF1 domain restored the SRC‐1/RXRα AF1 interaction. Our data suggest that Ki‐RAS mediated phosphorylation of the RXRα AF1 domain disrupts protein interactions important for 1,25 D‐mediated gene transcription. Supported by NIH award CA101113 to JCF.