Moreno Jacqueline, Krishnan Aruna V, Swami Srilatha, Nonn Larisa, Peehl Donna M, Feldman David
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5103, USA.
Cancer Res. 2005 Sep 1;65(17):7917-25. doi: 10.1158/0008-5472.CAN-05-1435.
Calcitriol exhibits antiproliferative and pro-differentiation effects in prostate cancer. Our goal is to further define the mechanisms underlying these actions. We studied established human prostate cancer cell lines and primary prostatic epithelial cells and showed that calcitriol regulated the expression of genes involved in the metabolism of prostaglandins (PGs), known stimulators of prostate cell growth. Calcitriol significantly repressed the mRNA and protein expression of prostaglandin endoperoxide synthase/cyclooxygenase-2 (COX-2), the key PG synthesis enzyme. Calcitriol also up-regulated the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme initiating PG catabolism. This dual action was associated with decreased prostaglandin E2 secretion into the conditioned media of prostate cancer cells exposed to calcitriol. Calcitriol also repressed the mRNA expression of the PG receptors EP2 and FP, providing a potential additional mechanism of suppression of the biological activity of PGs. Calcitriol treatment attenuated PG-mediated functional responses, including the stimulation of prostate cancer cell growth. The combination of calcitriol with nonsteroidal anti-inflammatory drugs (NSAIDs) synergistically acted to achieve significant prostate cancer cell growth inhibition at approximately 2 to 10 times lower concentrations of the drugs than when used alone. In conclusion, the regulation of PG metabolism and biological actions constitutes a novel pathway of calcitriol action that may contribute to its antiproliferative effects in prostate cells. We propose that a combination of calcitriol and nonselective NSAIDs might be a useful chemopreventive and/or therapeutic strategy in men with prostate cancer, as it would allow the use of lower concentrations of both drugs, thereby reducing their toxic side effects.
骨化三醇在前列腺癌中表现出抗增殖和促分化作用。我们的目标是进一步明确这些作用背后的机制。我们研究了已建立的人前列腺癌细胞系和原代前列腺上皮细胞，结果表明骨化三醇可调节参与前列腺素（PGs）代谢的基因表达，而前列腺素是已知的前列腺细胞生长刺激因子。骨化三醇显著抑制前列腺素内过氧化物合酶/环氧化酶-2（COX-2）这一关键PG合成酶的mRNA和蛋白表达。骨化三醇还上调了15-羟基前列腺素脱氢酶的表达，该酶启动PG的分解代谢。这种双重作用与暴露于骨化三醇的前列腺癌细胞条件培养基中前列腺素E2分泌减少有关。骨化三醇还抑制了PG受体EP2和FP的mRNA表达，为抑制PG生物活性提供了一种潜在的额外机制。骨化三醇处理减弱了PG介导的功能反应，包括对前列腺癌细胞生长的刺激。骨化三醇与非甾体抗炎药（NSAIDs）联合使用时，在比单独使用药物低约2至10倍的浓度下协同作用，实现了对前列腺癌细胞生长的显著抑制。总之，PG代谢和生物学作用的调节构成了骨化三醇作用的一条新途径，可能有助于其在前列腺细胞中的抗增殖作用。我们提出，骨化三醇与非选择性NSAIDs联合使用可能是前列腺癌男性患者有用的化学预防和/或治疗策略，因为这样可以使用较低浓度的两种药物，从而减少它们的毒副作用。
