The role of mevalonate pathway intermediates in erythropoietin receptor signal transduction and surface expression: studies in hematopoietic and nonhematopoietic cancers

Erythropoietin (Epo) acts through the erythropoietin receptor (EpoR) to influence survival, proliferation, and differentiation of erythroid progenitors. EpoR was recently found to be expressed in several cancers as well. The functional consequences of this expression are poorly understood but several findings suggest that EpoR contributes to the survival, migration, and drug resistance of cancer cells. The effects of Epo are mediated through activation of several signaling pathways including the Jak/Stat5 pathway and the Ras/Raf/MAPK pathway. The mevalonate pathway provides several products essential for cell function and survival. Cholesterol, ubiquinone, and dolichol are only few examples of such products. The isoprenoid intermediates, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), are also generated from the mevalonate pathway and are essential for the process of isoprenylation, which is an essential post-translational modification of several cellular proteins. Many of the isoprenylated proteins are members of the Ras superfamily of small GTPases. Epo activates several members of this family including Ras, Rac and Rap1. The aim of this proposal is to understand the interaction between the mevalonate biosynthetic pathway and EpoR signal transduction and to investigate the mechanism(s) through which the isoprenoid intermediates affects EpoR signaling. We have shown that two major isoprenoid derivatives, GGPP and dolichol, are essential for EpoR signal transduction and surface expression. Furthermore, we identified new roles for EpoR in cancers of non-erythroid origin and characterized signaling pathways involved and means to manipulate them for the ultimate goal of finding new avenues for cancer treatment.