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Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction.
- Source :
-
PloS one [PLoS One] 2015 Apr 15; Vol. 10 (4), pp. e0122458. Date of Electronic Publication: 2015 Apr 15 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- The aim of this study is to explore a cause-oriented therapy for patients with uterine cervical cancer that expresses erythropoietin (Epo) and its receptor (EpoR). Epo, by binding to EpoR, stimulates the proliferation and differentiation of erythroid progenitor cells into hemoglobin-containing red blood cells. In this study, we report that the HeLa cells in the xenografts expressed ε, γ, and α globins as well as myoglobin (Mb) to produce tetrameric α2ε2 and α2γ2 and monomeric Mb, most of which were significantly suppressed with an EpoR antagonist EMP9. Western blotting revealed that the EMP9 treatment inhibited the AKT-pAKT, MAPKs-pMAPKs, and STAT5-pSTAT5 signaling pathways. Moreover, the treatment induced apoptosis and suppression of the growth and inhibited the survival through disruption of the harmonized hemoprotein syntheses in the tumor cells concomitant with destruction of vascular nets in the xenografts. Furthermore, macrophages and natural killer (NK) cells with intense HIF-1α expression recruited significantly more in the degenerating foci of the xenografts. These findings were associated with the enhanced expressions of nNOS in the tumor cells and iNOS in macrophages and NK cells in the tumor sites. The treated tumor cells exhibited a substantial number of perforations on the cell surface, which indicates that the tumors were damaged by both the nNOS-induced nitric oxide (NO) production in the tumor cells as well as the iNOS-induced NO production in the innate immune cells. Taken together, these data suggest that HeLa cells constitutively acquire ε, γ and Mb synthetic capacity for their survival. Therefore, EMP9 treatment might be a cause-oriented and effective therapy for patients with squamous cell carcinoma of the uterine cervix.
- Subjects :
- Animals
Apoptosis drug effects
Blotting, Western
Cell Proliferation drug effects
Erythropoietin chemistry
Erythropoietin pharmacology
Gene Expression drug effects
HeLa Cells
Hemoglobins genetics
Heterografts metabolism
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinases metabolism
Neoplasms, Experimental genetics
Neoplasms, Experimental pathology
Peptides chemical synthesis
Proto-Oncogene Proteins c-akt metabolism
Receptors, Erythropoietin genetics
Receptors, Erythropoietin metabolism
Reverse Transcriptase Polymerase Chain Reaction
STAT5 Transcription Factor metabolism
Signal Transduction drug effects
Transplantation, Heterologous
Hemoglobins biosynthesis
Heterografts drug effects
Neoplasms, Experimental metabolism
Peptides pharmacology
Receptors, Erythropoietin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25874769
- Full Text :
- https://doi.org/10.1371/journal.pone.0122458