Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer
Helen E. Burston, … , Anne-Marie Mes-Masson, Robert Rottapel
Helen E. Burston, … , Anne-Marie Mes-Masson, Robert Rottapel
Published February 9, 2021
Citation Information: J Clin Invest. 2021;131(7):e142677. https://doi.org/10.1172/JCI142677.
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Research Article Oncology

Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer

Abstract

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.

Authors

Helen E. Burston, Oliver A. Kent, Laudine Communal, Molly L. Udaskin, Ren X. Sun, Kevin R. Brown, Euihye Jung, Kyle E. Francis, Jose La Rose, Joshua Lowitz, Ronny Drapkin, Anne-Marie Mes-Masson, Robert Rottapel

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Figure 7

Relaxin neutralizing monoclonal antibody abrogates HGSOC cell growth.

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Relaxin neutralizing monoclonal antibody abrogates HGSOC cell growth. (A...
(A) Growth of OVCAR8 and OVCAR5 treated with relaxin-neutralizing monoclonal antibody (m34-21) or isotype control. Error bars indicate mean ± SEM. n = 5. (B) Representative images of OVCAR8 and OVCAR5 treated with m34-21 or isotype control for 7 days. Scale bar: 10 μm. n = 5. (C) Viability of OVCAR8 treated with m34-21 or isotype control for 7 days. For panels C and F, box plots indicate the IQR of the data, and the central line shows the median. n = 5. ***P < 0.001, Student’s t test. (D) Growth of OVCAR8 and OVCAR5 treated with a sublethal dose of cisplatin (1.75 μM) alone or in combination with m34-21 or isotype control (50 μg/mL). n = 5. (E) Repopulating colonies formed following no treatment (–) or treatment with cisplatin (+Cis) alone (UT) or in combination with m34-21 (50 μg/mL). Scale bar: 10 μm. n = 5. (F) Quantification of the repopulating colony assay as described in E. Quantification was performed using ImageJ (NIH). ***P < 0.001, Student’s t test. n = 5.