Wang Lilin, Flanagan John N, Whitlatch Lyman W, Jamieson Daniel P, Holick Michael F, Chen Tai C
Department of Medicine, Endocrine Division, Boston University Medical Center, Boston, MA 02118, USA.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):127-30. doi: 10.1016/j.jsbmb.2004.03.091.
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.
越来越多的数据表明，1α,25-二羟基维生素D（1α,25(OH)₂D）的局部产生可能以自分泌方式在前列腺细胞中提供一种重要的细胞生长调节机制。此前，我们证明了在非癌细胞（PZHPV-7）和癌细胞（PC-3、DU145、LNCaP）中1α-羟化酶（1α-OHase）酶活性存在差异表达，这似乎与1α-OHase的mRNA合成及其启动子活性相关。由于已知表皮生长因子（EGF）通过自分泌和旁分泌环路调节前列腺细胞的增殖，而1α,25(OH)₂D抑制前列腺细胞增殖，我们研究了EGF是否也调节前列腺细胞中1α-OHase的表达。我们发现EGF上调了PZ-HPV-7细胞中1α-OHase的启动子活性和酶活性，并且1α,25(OH)₂D₃抑制了EGF依赖的1α-OHase酶活性上调。此外，丝裂原活化蛋白激酶激酶（MAPKK）抑制剂PD98059使EGF刺激的启动子活性降低了70%，这表明丝裂原活化蛋白激酶（MAPK）途径可能是EGF调节前列腺1α-OHase以增加1α,25(OH)₂D合成作为细胞生长反馈调节因子的一条途径。由于EGF对LNCaP细胞中的1α-OHase启动子活性没有影响，我们提出EGF刺激1α,25(OH)₂D合成的能力在癌细胞中可能被消除或减弱。
