Regulation of 25-hydroxyvitamin D-1alpha-hydroxylase by epidermal growth factor in prostate cells.
Accumulating data suggest that local production of 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D) could provide an important cell growth regulatory mechanism in an autocrine fashion in prostate cells. Previously, we demonstrated a differential expression of 1alpha-OHase enzymatic activity among noncancerous (PZHPV-7) and cancer cells (PC-3, DU145, LNCaP), which appears to correlate with 1alpha-OHase m-RNA synthesis and its promoter activities. Since it is well-established that EGF regulates the proliferation of prostate cells via autocrine and paracrine loops and 1alpha,25(OH)(2)D inhibites prostate cell proliferation, we investigated if EGF also regulated 1alpha-OHase expression in prostate cells. We found that EGF upregulated 1alpha-OHase promoter activity and enzyme activity in PZ-HPV-7 and that 1alpha,25(OH)(2)D(3) inhibited EGF-dependent up-regulation of 1alpha-OHase enzymatic activity. Moreover, the EGF-stimulated promoter activity was inhibited 70% by the MAPKK inhibitor, PD98059, suggesting that the MAPK pathway may be one pathway involved in the regulation of prostatic 1alpha-OHase by EGF to increase1alpha,25(OH)(2)D synthesis as a feedback regulator of cell growth. Because EGF has no effect on 1alpha-OHase promoter activity in LNCaP cells, we propose that the ability of EGF to stimulate 1alpha,25(OH)(2)D synthesis may be abolished or diminished in cancer cells.
Wang
Lilin
L
Department of Medicine, Endocrine Division, Boston University Medical Center, Boston, MA 02118, USA.
Flanagan
John N
JN
Whitlatch
Lyman W
LW
Jamieson
Daniel P
DP
Holick
Michael F
MF
Chen
Tai C
TC
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000201:enzymology* / Q000473:pathology
D004815:Epidermal Growth Factor; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase