Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer
| Autor: | Anne-Marie Mes-Masson, Molly L. Udaskin, Ren X. Sun, Euihye Jung, Kevin R. Brown, Laudine Communal, Jose La Rose, Ronny Drapkin, Joshua K. Lowitz, Kyle E. Francis, Helen E. Burston, Oliver A. Kent, Robert Rottapel |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway endocrine system Carcinogenesis MAP Kinase Signaling System Biology medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor medicine Animals Humans Viability assay STAT3 Autocrine signalling Wnt Signaling Pathway Relaxin Ovarian Neoplasms Cell growth urogenital system Wnt signaling pathway General Medicine Neoplasm Proteins body regions Autocrine Communication 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research Female hormones hormone substitutes and hormone antagonists Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | Ovarian cancer (OC) is the most deadly gynecological malignancy, with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, using cell lines and xenograft models, we demonstrate that relaxin and its associated GPCR RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation, and viability. We determined that relaxin signaling activates expression of prooncogenic pathways, including RHO, MAPK, Wnt, and Notch. We found that relaxin is detectable in patient-derived OC tumors, ascites, and serum. Further, inflammatory cytokines IL-6 and TNF-α activated transcription of relaxin via recruitment of STAT3 and NF-κB to the proximal promoter, initiating an autocrine feedback loop that potentiated expression. Inhibition of RXFP1 or relaxin increased cisplatin sensitivity of OC cell lines and abrogated in vivo tumor formation. Finally, we demonstrate that a relaxin-neutralizing antibody reduced OC cell viability and sensitized cells to cisplatin. Collectively, these data identify the relaxin/RXFP1 autocrine loop as a therapeutic vulnerability in OC. |
| Databáze: | OpenAIRE |
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