Significance of Erythropoietin Receptor Antagonist EMP9 in Cancers.

We have clarified that cancer cells express their own erythropoietin (Epo) and its receptor (EpoR) mRNA levels, and the respective proteins, which are under the control of Epo-EpoR signaling. Then we explored to inhibit the Epo-EpoR signaling with an EpoR antagonist Epo mimetic peptide 9 (EMP9) that is a derivative of an Epo-mimicking peptide EMP1. In the study of the cancer cell lines in vitro, rhEpo accelerated the cancer cell growth, whereas the EMP9 inhibited the cell growth along with the inhibition of STAT5 tyrosine phosphorylation. Moreover, in vitro study of surgically resected histoculture of lung cancers revealed that EMP9 diminishes the expression of myoglobin in the cancer cells and destroys the feeding vessels. Additionally, in the xenografts of lung cancer histoculture, the EMP9 destroyed the xenografts by inducing apoptosis and suppressing proliferation of cancer cells in concomitant with macrophage accumulation. Furthermore, two types of perforations were detected in their cytoplasm: the one is mediated by nNOS in the cancer cells and the other one is by iNOS in the innate immune cells. These findings suggest that the inhibition of the Epo-EpoR signaling by EMP9 induces the cancer cell death that is mediated by the apoptosis and calcification of the cancer cells as well as the oxygen deficiency through the feeding vessels. Taken together, EMP9-based therapy may be a promising strategy to treat cancer patients.