A functional Epo-EpoR axis modulates the growth and survival of prostate cancer cells

5094 A growing number of reports have identified erythropoietin receptors (EpoR) on a variety of cancer-derived cell lines and primary cancer cells, including those of prostate cancer (CaP). However, the functional status of the EpoR on cancer cells remains a matter of some dispute. The publication of several large clinical trials suggesting a direct effect of erythropoietin (Epo) on the growth and survival of primary tumors adds further importance to the question of whether the EpoR on cancer cells are functional. We have reported previously that human prostate cancer (CaP) cell lines and primary prostate cancer cells express functional EpoR and that exogenous Epo stimulates increased cell proliferation and STAT5 phosphorylation (Feldman et al 2006, The Prostate 66:135). Moreover, we have demonstrated that Epo stimulates the growth of CaP cell colonies in soft agar culture in a dose-dependent manner. Soft agar colony formation is considered to be an in vitro model for predicted in vivo tumorigenicity of cancer cells, suggesting that Epo may stimulate the growth of prostate tumors in vivo. We now demonstrate 1) that chronic Epo-treatment of prostate cancer cells results in cells with increased resistance to docetaxel and 2) that each of the transformed and tumorigenic prostate cancer cell lines that we have examined expresses high levels of the Epo gene and produces biologically active Epo endogenously. The co-expression of functional receptor and biologically-active ligand in the cells has led us to hypothesize that an autocrine-paracrine mechanism, driven by endogenous Epo, may play a significant role in the growth and progression of prostate cancer. To test our hypothesis we have knocked-down the EpoR on CaP cells (=EpoRKD) by stable transfection with shRNAs and have isolated several clonal populations of EpoRKD cells. The cells that lack EpoR expression grow significantly more slowly than their EpoR-bearing counterparts in monolayer culture and produce fewer, smaller colonies in soft agar. Further, the EpoRKD cells neither respond to exogenous Epo mitogenically nor exhibit Epo-induced signaling. Taken together, our data support the coordinated regulation of a functional Epo-EpoR axis in CaP cells that is integral to the growth and progression of prostate cancer. The identification of a functional Epo - EpoR axis on CaP cells introduces the EpoR as a novel therapeutic target in CaP and may suggest the potential need for re-evaluation of the use of rhEpo as an adjuvant to chemotherapy in at least some CaP patients.