An Erythropoietin Autocrine/Paracrine Axis Modulates the Growth and Survival of Human Prostate Cancer Cells

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)