Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction.
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 b...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4398449?pdf=render |
| _version_ | 1818942589807624192 |
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| author | Yoshiko Yasuda Mitsugu Fujita Eiji Koike Koshiro Obata Mitsuru Shiota Yasushi Kotani Terunaga Musha Sachiyo Tsuji-Kawahara Takao Satou Seiji Masuda Junko Okano Harufumi Yamasaki Katsumi Okumoto Tadao Uesugi Shinichi Nakao Hiroshi Hoshiai Masaki Mandai |
| author_facet | Yoshiko Yasuda Mitsugu Fujita Eiji Koike Koshiro Obata Mitsuru Shiota Yasushi Kotani Terunaga Musha Sachiyo Tsuji-Kawahara Takao Satou Seiji Masuda Junko Okano Harufumi Yamasaki Katsumi Okumoto Tadao Uesugi Shinichi Nakao Hiroshi Hoshiai Masaki Mandai |
| author_sort | Yoshiko Yasuda |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T07:13:50Z |
| format | Article |
| id | doaj.art-7ddc689efd38438eb46616ffb962a3bd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T07:13:50Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7ddc689efd38438eb46616ffb962a3bd2022-12-21T19:48:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012245810.1371/journal.pone.0122458Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction.Yoshiko YasudaMitsugu FujitaEiji KoikeKoshiro ObataMitsuru ShiotaYasushi KotaniTerunaga MushaSachiyo Tsuji-KawaharaTakao SatouSeiji MasudaJunko OkanoHarufumi YamasakiKatsumi OkumotoTadao UesugiShinichi NakaoHiroshi HoshiaiMasaki MandaiThe 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.http://europepmc.org/articles/PMC4398449?pdf=render |
| spellingShingle | Yoshiko Yasuda Mitsugu Fujita Eiji Koike Koshiro Obata Mitsuru Shiota Yasushi Kotani Terunaga Musha Sachiyo Tsuji-Kawahara Takao Satou Seiji Masuda Junko Okano Harufumi Yamasaki Katsumi Okumoto Tadao Uesugi Shinichi Nakao Hiroshi Hoshiai Masaki Mandai Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction. PLoS ONE |
| title | Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction. |
| title_full | Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction. |
| title_fullStr | Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction. |
| title_full_unstemmed | Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction. |
| title_short | Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction. |
| title_sort | erythropoietin receptor antagonist suppressed ectopic hemoglobin synthesis in xenografts of hela cells to promote their destruction |
| url | http://europepmc.org/articles/PMC4398449?pdf=render |
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