Recombinant human erythropoietin stimulates melanoma tumor growth through activation of initiation factor eIF4E.

Annabelle Julius,Raymond L Yung,Anjali Desai

doi:10.18632/oncotarget.16331

Abstract

Recombinant human erythropoietin (EPO) is standard treatment for anemia in cancer patients. Recent clinical trials suggest that EPO may accelerate tumor progression and increase mortality. However, the evidence supporting a growth-promoting effect of EPO has remained controversial. Employing an in vivo model of B16 murine melanoma, we observed that administration of EPO to tumor bearing C57BL/6 mice resulted in pronounced acceleration of melanoma growth. Our in vitro studies demonstrate that B16 murine melanoma cells express EPOR, both at the protein and mRNA levels. Interestingly, expression of EPOR was retained in the established tumors. EPO stimulation of B16 cells enhanced proliferation and protein synthesis rates, and correlated with activation of the receptor associated Janus kinase 2 (Jak2) as well as phosphorylation of extracellular signal–regulated kinase (Erk) 1/2 and Akt kinases. Treatment with EPO and Jak-2 antagonists significantly inhibited EPO-mediated B16 cell proliferation. Moreover, EPO dose-dependently induced the phosphorylation and activation of the translation initiation factor eIF4E as well as the phosphorylation of its repressor, the eIF4E binding protein 4E-BP1. Finally, using eIF4E small interfering RNA (siRNA), we observed that EPO-mediated stimulation of B16 cell proliferation is eIF4E-dependent. Our results indicate that EPO exerts a powerful stimulatory effect on cell proliferation and de novo protein synthesis in melanoma cells through activation of the initiation factor eIF4E.

Highlights

Recombinant human erythropoietin is a glycoprotein hormone that serves as the primary regulator of red blood cell production by stimulating growth, preventing apoptosis, and inducing differentiation of erythroid progenitor cells
Our results indicate that EPO exerts a powerful stimulatory effect on cell proliferation and de novo protein synthesis in melanoma cells through activation of the initiation factor eIF4E
While treatment with EPO has significantly reduced the need for transfusions and has improved the overall quality of life for many cancer patients, reports from several recent clinical trials suggest that therapeutic doses of EPO or related erythropoiesis-stimulating agents (ESAs) may promote later tumor metastasis and mortality [1]

Summary

Introduction

Recombinant human erythropoietin is a glycoprotein hormone that serves as the primary regulator of red blood cell production by stimulating growth, preventing apoptosis, and inducing differentiation of erythroid progenitor cells. Since EPO was first purified from urine more than three decades ago, its recombinant form has become widely used for the treatment of anemia associated with chronic kidney disease, human immunodeficiency acquired immune deficiency syndrome (HIV/AIDS), and cancer. While treatment with EPO has significantly reduced the need for transfusions and has improved the overall quality of life for many cancer patients, reports from several recent clinical trials suggest that therapeutic doses of EPO or related erythropoiesis-stimulating agents (ESAs) may promote later tumor metastasis and mortality [1]. There is accumulating evidence that the adverse effects of EPO may be a consequence of the ubiquitous expression of functional EPORs in cancer cells. Mirmohammadsadegh et al demonstrated that EPOR is expressed in human melanoma specimens and expression is significantly higher is melanoma metastasis compared to nevi and www.impactjournals.com/oncotarget primary melanoma suggesting an association with disease progression and EPOR expression [5]

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