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

• Published in: Oncogene Vol. 37; no. 35; pp. 4809 - 4820
• Main Authors: Rada, Miran, Nallanthighal, Sameera, Cha, Jennifer, Ryan, Kerry, Sage, Jessica, Eldred, Catherine, Ullo, Maria, Orsulic, Sandra, Cheon, Dong-Joo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/106; 42/89; 631/67/1517/1709; 631/67/327; 82/29; 96/2; 96/95; AKT protein; Animal models; Animals; Antineoplastic agents; Apoptosis; Apoptosis - physiology; Cancer cells; Cancer research; Cancer treatment; Care and treatment; Cell Biology; Cell Line, Tumor; Cellular proteins; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Collagen; Collagen Type XI - metabolism; Computer memory; Development and progression; Drug resistance; Drug Resistance, Neoplasm - physiology; Extracellular matrix; Female; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Genes; Genetic aspects; Health aspects; Human Genetics; Humans; IAP protein; Inhibitor of Apoptosis Proteins - metabolism; Integrins; Internal Medicine; Medicine; Medicine & Public Health; Mice; Mice, Nude; NF-κB protein; Oncology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Prognosis; Proteins; Recurrence (Disease); Signal transduction; Signal Transduction - physiology; Therapeutic applications; Xenografts; XIAP protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0297-x

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.