Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA.
Horm Cancer. 2010 Aug;1(4):167-76. doi: 10.1007/s12672-010-0023-9.
The high mortality rates associated with ovarian cancer are largely due to a lack of highly effective treatment options for advanced stage disease; a time when initial diagnosis most commonly occurs. Recent evidence suggests that the steroid hormone, progesterone, may possess anti-tumorigenic properties. With the discovery of a new class of membrane-bound progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor (PAQR) gene family in the ovary, there are undefined mechanisms by which progesterone may inhibit tumor progression. Therefore, our goal was to define potential mPR-dependent signaling mechanisms operative in ovarian cancer cells. We detected abundant mPRα (PAQR7), mPRβ (PAQR8), and mPRγ (PAQR5), but not classical nuclear PR (A or B isoforms) mRNA expression and mPRα protein expression in a panel of commonly used ovarian cancer cell lines. In contrast to mPR action in breast cancer cells, progesterone alone failed to induce changes in cyclic adenosine monophosphate (cAMP) levels in ovarian cancer cells. However, progesterone enhanced cAMP production by β(1,2)-adrenergic receptors and increased isoproterenol-induced transcription from a cAMP response element (CRE)-driven reporter gene. Independently of β-adrenergic signaling, we additionally observed activation of both JNK1/2 and p38 MAPK in response to progesterone alone. This finding was supported by the results of a screen for potential mPR gene targets. Progesterone induced a significant increase in transcription of the pro-apoptotic marker BAX, whose activity and expression has been linked to JNK1/2 and p38 signaling. Inhibitors of JNK, but not p38, blocked progesterone-induced BAX expression. Taken together, these observations implicate at least two distinct signaling pathways that may be utilized by mPRs in ovarian cancer cells that exhibit regulatory genomic changes. These studies on mPR signaling in ovarian cancer lay the foundation for future work aimed at understanding how progesterone exerts its anti-tumorigenic effects in the ovary and suggest that pharmacologic activation of mPRs, abundantly expressed in ovarian cancers, may provide a new treatment option for patients with advanced stage disease.
卵巢癌的高死亡率在很大程度上是由于缺乏针对晚期疾病的高度有效治疗方法；而晚期疾病通常是初次诊断的阶段。最近的证据表明，甾体激素孕酮可能具有抗肿瘤特性。由于在卵巢中发现了一类新的膜结合孕酮受体（mPR），属于孕激素和脂联素受体（PAQR）基因家族，孕酮可能通过尚未确定的机制抑制肿瘤进展。因此，我们的目标是确定孕酮在卵巢癌细胞中可能发挥作用的潜在 mPR 依赖性信号机制。我们在一组常用的卵巢癌细胞系中检测到丰富的 mPRα（PAQR7）、mPRβ（PAQR8）和 mPRγ（PAQR5），但没有检测到经典的核 PR（A 或 B 同种型）mRNA 表达和 mPRα 蛋白表达。与乳腺癌细胞中 mPR 的作用相反，孕酮单独作用不能改变卵巢癌细胞中环磷酸腺苷（cAMP）水平。然而，孕酮增强了β（1,2）-肾上腺素能受体诱导的 cAMP 产生，并增加了异丙肾上腺素诱导的 cAMP 反应元件（CRE）驱动报告基因的转录。独立于β-肾上腺素能信号，我们还观察到孕酮单独作用时 JNK1/2 和 p38 MAPK 的激活。这一发现得到了潜在 mPR 基因靶点筛选结果的支持。孕酮诱导促凋亡标志物 BAX 的转录显著增加，BAX 的活性和表达与 JNK1/2 和 p38 信号有关。JNK 的抑制剂，但不是 p38 的抑制剂，阻断了孕酮诱导的 BAX 表达。综上所述，这些观察结果表明，至少有两种不同的信号通路可能被卵巢癌细胞中的 mPR 利用，这些细胞表现出调节性基因组变化。这些关于 mPR 信号在卵巢癌中的研究为未来旨在了解孕酮在卵巢中发挥其抗肿瘤作用的工作奠定了基础，并表明在卵巢癌中大量表达的 mPR 的药理学激活可能为晚期疾病患者提供新的治疗选择。
