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Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer

Oncogenevolume 37pages48094820 (2018) | Download Citation

Abstract

Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells. Mechanistically, we show that COL11A1 activates Src-PI3K/Akt-NF-kB signaling to induce the expression of three inhibitor apoptosis proteins (IAPs), including XIAP, BIRC2, and BIRC3. Genetic and pharmacological inhibition of XIAP, BIRC2, and BIRC3 is sufficient to restore cisplatin-induced apoptosis in ovarian cancer cells in the presence of COL11A1 in ovarian cancer cells and xenograft mouse models, respectively. We also show that the components of COL11A1- integrin α1β1/DDR2- Src-PI3K/Akt-NF-kB-IAP signaling pathway serve as poor prognosis markers in ovarian cancer patients. Taken together, our results suggest novel mechanisms by which COL11A1 confers cisplatin resistance in ovarian cancer. Our study also uncovers IAPs as promising therapeutic targets to reduce cisplatin resistance in ovarian cancer, particularly in recurrent ovarian cancer expressing high levels of COL11A1.

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Acknowledgements

We thank Drs. Robert C. Bast, Michael DiPersio, and Paula McKeown-Longo for insightful discussions and critical readings of the manuscript; Dr. Nikki Cheng for CAF cells. D.-J.C. is supported by the startup fund from the Albany Medical College, the Ovarian Cancer Research Fund Ann Schreiber Mentored Investigator Award, and the AACR Gertrude B. Elion Cancer Research Award.

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Affiliations

  1. Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, 12208, USA

    • Miran Rada
    • , Sameera Nallanthighal
    • , Jennifer Cha
    • , Kerry Ryan
    • , Jessica Sage
    • , Catherine Eldred
    • , Maria Ullo
    •  & Dong-Joo Cheon
  2. School of Science, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    • Jennifer Cha
  3. Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    • Sandra Orsulic

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The authors declare that they have no conflict of interest.

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Correspondence to Dong-Joo Cheon.

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DOI

https://doi.org/10.1038/s41388-018-0297-x