Accession Number:

ADA446970

Title:

Molecular Mechanism for Prostate Cancer Resistance to the Anti-Tumor Activity

Descriptive Note:

Annual rept. 1 Nov 2004-31 Oct 2005

Corporate Author:

LELAND STANFORD JUNIOR UNIV STANFORD CA

Personal Author(s):

Report Date:

2005-11-01

Pagination or Media Count:

44.0

Abstract:

The original purpose of this research, as proposed in the statement of work, was to determine the mechanism by which prostate cancer PCa cells become resistant to the anti-tumor activity of vitamin D. The proposal focused on a PCa-specific deficiency in a key vitamin D metabolizing enzyme, 1alpha-hydroxylase 1alphaOH. We encountered unforeseen difficulties with one of the key techniques in the original proposal. Therefore we decided to focus on vitamin D target genes, whose expression would be effected downstream of 1OH bioactivation of vitamin D. Using normal human prostatic epithelial cells and prostate cancer cell lines, we examined the role of map kinase phosphatase 5 MKP5, a recently discovered target gene of vitamin D, in mediating anti-tumor activities. Upregulation of MKP5 mRNA by 1,25- dihydroxyvitamin D3 1,25D was found to be dependent upon the vitamin D receptor VDR and the MKP5 promoter contains a putative positive vitamin D response element that associates with the VDR upon treatment with 1,25D. MKP5 dephosphorylatesinactivates the stress activated protein kinase p38. Interestingly, in the prostate cancer cell lines LNCaP, PC-3 and DU 145, 1,25D did not upregulate MKP5 or inactivate p38. Treatment of prostate cells with 1,25D inhibited basal and stimulated phosphorylation of p38, and MKP5-siRNA blocked this effect. We next investigated the effect of 1,25D on expression of interleukin-6 IL-6, a downstream target of activated p38. IL-6 is an inflammatory cytokine and inflammation has been implicated in the initiation and promotion of prostate cancer. We found that 1,25D inhibited both UV- and tumor necrosis factor TNF-alpha-stimulated IL-6 production in normal cells via p38 inhibition.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE