An Erythropoietin Autocrine/Paracrine Axis Modulates the Growth and Survival of Human Prostate Cancer Cells
An Erythropoietin Autocrine/Paracrine Axis Modulates the Growth and Survival of Human Prostate Cancer Cells
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DOI：
10.1158/1541-7786.mcr-08-0243
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发表时间：
2009-07-01
影响因子：
5.2
通讯作者：
Feldman, Laurie
中科院分区：
文献类型：
--
作者：
Jeong, Jee-Yeong;Hoxhaj, Gerta;Feldman, Laurie
促红细胞生成素受体已在多种癌症衍生的细胞系和原代癌细胞（包括前列腺癌的那些）上被鉴定。这些造血细胞外促红细胞生成素受体的功能状态仍然是一个有争议的问题。几个重要的临床试验表明促红细胞生成素对原发性肿瘤的生长和存活的直接作用的出版物增加了促红细胞生成素受体在癌细胞上是否有功能的问题的进一步重要性。我们以前曾报道，人前列腺癌细胞系和原代前列腺癌细胞表达功能性促红细胞生成素受体，通过增加细胞增殖和STAT 5磷酸化来响应外源性促红细胞生成素。我们现在发现前列腺癌细胞系同时表达EPO基因和具有生物活性的促红细胞生成素。功能性受体和生物活性配体在细胞中的共表达使我们假设由内源性促红细胞生成素驱动的自分泌/旁分泌机制可能调节前列腺癌的生长和进展。为了验证我们的假设，我们已经敲低，独立地，促红细胞生成素受体和促红细胞生成素的前列腺癌细胞转染短发夹RNA。在单层培养中，促红细胞生成素受体敲除细胞比其携带促红细胞生成素受体的对应物生长显著更慢，在软琼脂中产生更少、更小的集落，并且不表现出促红细胞生成素诱导的信号传导。促红细胞生成素敲除细胞表现出明显较慢的生长速率，这可以通过用鼠促红细胞生成素基因转染细胞来恢复。总之，我们的数据表明，协调调节功能性促红细胞生成素/促红细胞生成素受体轴在前列腺癌细胞中可能是不可或缺的前列腺癌的生长和进展。(Mol Cancer Res 2009;7（7）：1150-7）
Erythropoietin receptors have been identified on a variety of cancer-derived cell lines and primary cancer cells, including those of prostate cancer. The functional status of these extrahematopoietic erythropoietin receptors remains a matter of some dispute. The publication of several important clinical trials suggesting a direct effect of erythropoietin on the growth and survival of primary tumors adds further importance to the question of whether erythropoietin receptors on cancer cells are functional. We have reported previously that human prostate cancer cell lines and primary prostate cancer cells express functional erythropoietin receptors that respond to exogenous erythropoietin by increased cell proliferation and STAT5 phosphorylation. We now show that prostate cancer cell lines express both the EPO gene and the biologically active erythropoietin. The coexpression of functional receptor and biologically active ligand in the cells has led us to hypothesize an autocrine/paracrine mechanism, driven by endogenous erythropoietin, which may modulate the growth and progression of prostate cancer. To test our hypothesis, we have knocked down, independently, erythropoietin receptor and erythropoietin on prostate cancer cells by transfection with short hairpin RNAs. Erythropoietin receptor knockdown cells grow significantly more slowly than their erythropoietin receptor-bearing counterparts in monolayer culture, produce fewer, smaller colonies in soft agar, and do not exhibit erythropoietin-induced signaling. Erythropoietin knockdown cells exhibit dramatically slower rates of growth, which could be restored by transfecting the cells with a murine erythropoietin gene. Taken together, our data suggest that the coordinated regulation of a functional erythropoietin/erythropoietin receptor axis in prostate cancer cells may be integral to the growth and progression of prostate cancer. (Mol Cancer Res 2009;7(7):1150-7)