Expression of membrane progesterone receptors (mPR/PAQR) in ovarian cancer cells: implications for progesterone-induced signaling events.
Expression of membrane progesterone receptors (mPR/PAQR) in ovarian cancer cells: implications for progesterone-induced signaling events.
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DOI：
10.1007/s12672-010-0023-9
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发表时间：
2010-08
影响因子：
3
通讯作者：
Lange CA
中科院分区：
文献类型：
--
作者：
Charles NJ;Thomas P;Lange CA
与卵巢癌相关的高死亡率在很大程度上是由于缺乏对晚期疾病的高度有效的治疗选择；这一时期最常见的是初步诊断。最近的证据表明，类固醇激素黄体酮可能具有抗肿瘤特性。随着孕激素和ADIPOQ受体(PAQR)基因家族中一类新的膜结合型孕激素受体(MPR)在卵巢中的发现，孕酮抑制肿瘤进展的机制尚不明确。因此，我们的目标是确定在卵巢癌细胞中潜在的MPR依赖的信号机制。我们在一组常用的卵巢癌细胞系中检测到了丰富的mprα(PAQR7)、mprβ(PQR8)和mprγ(PQR5)，但没有检测到经典的核PR(A或B亚型)α和mpr DNA蛋白的表达。与乳腺癌细胞中MPR的作用相反，黄体酮本身并不能诱导卵巢癌细胞中环磷酸腺苷(CAMP)水平的变化。然而，孕酮通过β1，2-肾上腺素能受体增加cAMP的产生，并增加异丙肾上腺素诱导的cAMP反应元件(CAMP)驱动报告基因的转录。除了β-肾上腺素能信号外，我们还观察到JNK1/2和p38MAPK单独对孕酮的反应。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转录显著增加，Bax的活性和表达与JNK1/2和p38信号转导有关。JNK的抑制剂，而不是p38，阻断了孕酮诱导的Bax的表达。综上所述，这些观察结果至少暗示了两条不同的信号通路，它们可能被MPR用于卵巢癌细胞的基因组调节变化。这些关于卵巢癌中MPR信号转导的研究为进一步了解孕酮如何在卵巢中发挥抗肿瘤作用奠定了基础，并提示在卵巢癌中大量表达的MPR的药物激活可能为晚期疾病患者提供一种新的治疗选择。
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 β1,2-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.