Functional erythropoietin autocrine loop in melanoma.
Although erythropoietin (Epo) is a known stimulator of erythropoiesis, recent evidence suggests that its biological functions are not confined to hematopoietic cells. To elucidate the role of Epo and erythropoietin receptor (EpoR) in melanoma, we examined the expression and function of these proteins in melanocytes and melanoma cells. We found increased expression of Epo in melanoma cells compared to melanocyte in vitro. EpoR was also strongly expressed in all of the melanoma cell lines and two of the three melanocyte cell lines examined. Epo expression was significantly higher in melanoma than in benign nevi as determined by immunohistochemistry. Although melanoma cells secreted Epo in normoxic condition in vitro, hypoxia and CoCl(2) treatment increased Epo secretion. EpoR in melanoma cells was functional, because exogenous Epo increased melanoma resistance to hypoxic stress, pretreatment of melanoma cells with Epo significantly increased resistance to dacarbazine treatment, and Epo increased the phosphorylation of EpoR, RAF, and MEK. In conclusion, we demonstrated constitutive expression of Epo and EpoR as well as autonomous secretion of Epo by melanoma cells, indicating a novel autocrine loop of Epo in melanoma. The results suggest that the autocrine and paracrine functions of Epo might play a role in malignant transformation of melanocytes and in the survival of melanoma cells in hypoxia and other adverse conditions.
Kumar
Suresh M
SM
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Acs
Geza
G
Fang
Dong
D
Herlyn
Meenhard
M
Elder
David E
DE
Xu
Xiaowei
X
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003035:Cobalt / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000737:chemistry*; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014343:Trypan Blue / Q000494:pharmacology
D004396:Coloring Agents; D017077:Culture Media, Conditioned; D017467:Receptors, Erythropoietin; D013778:Tetrazolium Salts; D013844:Thiazoles; D004921:Erythropoietin; D003035:Cobalt; C022616:thiazolyl blue; C018021:cobaltous chloride; D014343:Trypan Blue
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