Abstract
We examined the effect of blocking the erythropoietin (Epo) signaling using an anti-Epo antibody, soluble form of Epo receptor (sEpoR) capable of binding to Epo or EpoR antagonist, and proved to be effective against xenografts of female reproductive organ malignancies and of cancer cell lines in nude mice. We transfected seven cancer cell lines of various origins to express constitutively active sEpoR, and examined their tumorigenesis in nude mice. Suppression of the tumor growth, decrease in viable and proliferating cells and reduction of vascular density were seen individually in all xenografts of transfected cell lines compared with the controls. Quantitative RT-PCR analyses showed that expression levels of Epo, EpoR, ?1A-adrenaline receptor (?1A-ADR) and muscalinic acetylcholine receptor subunit 3 mRNAs (m3-AchR) were higher in the majority of the wild-type xenografts than in the corresponding cell lines except for A549. In some of the transfected xenografts, EpoR, ?1A-ADR and m3-AchR mRNAs were down-regulated. Western blot analyses revealed that the constitutively activated ERK1/2MAPK was discernible in the majority of non-transfected cell lines and was reduced in the transfected cell lines. However, it was regained after exposure to acetylcholine and/or noradrenaline. These findings suggest that constitutively active sEpoR can effectively destroy the xenografts but signals from the autonomic neurotransmitters of the host produced under stress may interfere with this antitumor activity.
Highlights
Erythropoietin (Epo), a principal cytokine involved in erythropoiesis, has been reported to promote the growth of malignant tumors by binding to its receptor (EpoR) through both autocrine stimulation of malignant cells themselves and paracrine route to the feeding microvessels due to the expression of both transcripts for Epo and erythropoietin receptor (EpoR) mRNA in very many cancers [1,2,3,4] and for EpoR mRNA in the human endothelial cells of vein and artery [5]
The malignant cells expressing EpoR through blockade of Epo signaling appear to die by a mechanism similar to that seen in HCD 57 cell line, the survival of which depends entirely on the Epo signal [30], in which deprival of Epo induces the reduction of receptor internalization leaving EpoR in the cytoplasmic membrane
The population of dead cells was significantly higher than in each control xenograft (Figure 4, P < 0.001) and when the cells with chromatin-condensed nuclei that are suggestive of precursor of apoptotic death were added, the viability of the majority of transfected xenografts was less than 50 %, showing sSBC3, sA549, sPC-3, sP39, sHepG2, sSCH and sHeLa xenografts in high reduction order
Summary
Erythropoietin (Epo), a principal cytokine involved in erythropoiesis, has been reported to promote the growth of malignant tumors by binding to its receptor (EpoR) through both autocrine stimulation of malignant cells themselves and paracrine route to the feeding microvessels due to the expression of both transcripts for Epo and EpoR mRNA in very many cancers [1,2,3,4] and for EpoR mRNA in the human endothelial cells of vein and artery [5]. The JAK2 and STAT5 route is detected in female reproductive organ malignancies [6], in xenografts of melanoma and stomach choriocarcinoma cell lines [2] and in a prostate cancer cell line [18]; and, the ERK/MAPK route is seen in mammary carcinoma [8,9] and astrocytoma [19]. Both the STAT5 and the AKT routes are in operation in neuroblastoma cells [20]
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