title: Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction.
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.
authors: Departments of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Yoshiko
authors: Y
authors: Yasuda
authors: Departments of Microbiology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Mitsugu
authors: M
authors: Fujita
authors: Departments of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Eiji
authors: E
authors: Koike
authors: Department of Obstetrics and Gynecology, Nara Hospital Kinki University Faculty of Medicine, Ikoma, Nara, Japan.
authors: Koshiro
authors: K
authors: Obata
authors: Department of Gynecological Oncology, Kawasaki Medical University, Kurashiki, Okayama, Japan.
authors: Mitsuru
authors: M
authors: Shiota
authors: Departments of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Yasushi
authors: Y
authors: Kotani
authors: Department of Gynecology, Medicalcourt Hachinohe West Hospital, Hachinohe, Aomori, Japan.
authors: Terunaga
authors: T
authors: Musha
authors: Departments of Immunology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Sachiyo
authors: S
authors: Tsuji-Kawahara
authors: Departments of Pathology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Takao
authors: T
authors: Satou
authors: Laboratory of Molecular Biology of Bioresponse, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan.
authors: Seiji
authors: S
authors: Masuda
authors: Division of Anatomy and Cell Biology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors: Junko
authors: J
authors: Okano
authors: Departments of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Harufumi
authors: H
authors: Yamasaki
authors: Lifescience Institute, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Katsumi
authors: K
authors: Okumoto
authors: Departments of Pathology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Tadao
authors: T
authors: Uesugi
authors: Departments of Anesthesiology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Shinichi
authors: S
authors: Nakao
authors: Departments of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Hiroshi
authors: H
authors: Hoshiai
authors: Departments of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Masaki
authors: M
authors: Mandai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004921:Erythropoietin / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006454:Hemoglobins / Q000096:biosynthesis* / Q000235:genetics; D064593:Heterografts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D006454:Hemoglobins; D010455:Peptides; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases