Ovarian cancer (OC) is the most deadly gynaecological malignancy with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces aggressive cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, we demonstrate that relaxin and its associated G-protein coupled receptor RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation and viability. We have found that relaxin signaling activates expression of pro-oncogenic pathways including RHO, MAPK, Wnt, and Notch. We find that relaxin is detectable in OC tumors, ascites and serum. Further, inflammatory cytokines IL-6 and TNF-α activate transcription of relaxin via recruitment of STAT3 and NFκB to the proximal promoter initiating an autocrine feedback loop that potentiates expression. Inhibition of RXFP1 or relaxin increases cisplatin sensitivity of OC cell lines and abrogates in vivo tumor formation. Finally, we demonstrate that a relaxin neutralizing antibody reduces OC cell viability and sensitizes cells to cisplatin. Collectively, targeting relaxin-RXFP1 signaling offers a potential new therapeutic strategy for OC.

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