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.

中文翻译：

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凋亡蛋白（IAPs）抑制剂介导卵巢癌中的XI型胶原1α驱动的顺铂耐药性。

尽管顺铂耐药性是治疗卵巢癌的主要挑战，但尚不完全了解顺铂耐药性的确切机制。XI型胶原蛋白1（COL11A1）是一种编码细胞外基质的小纤维胶原蛋白的基因，被认为是顺铂耐药性卵巢癌和复发性卵巢癌中最上调的基因之一。但是，COL11A1在顺铂耐药性中的确切功能尚不清楚。在这里，我们证明COL11A1与整联蛋白α1β1和盘状蛋白结构域受体2（DDR2）结合并激活下游信号通路，以抑制顺铂诱导的卵巢癌细胞凋亡。从机制上讲，我们显示COL11A1激活Src-PI3K / Akt-NF-kB信号传导，以诱导表达三种抑制剂凋亡蛋白（IAP），包括XIAP，BIRC2和BIRC3。XIAP，BIRC2和BIRC3的遗传和药理学抑制作用足以在卵巢癌细胞和异种移植小鼠模型中分别在COL11A1存在的情况下恢复顺铂诱导的卵巢癌细胞凋亡。我们还显示，COL11A1-整合素α1β1/ DDR2- Src-PI3K / Akt-NF-kB-IAP信号通路的成分在卵巢癌患者中作为不良的预后标志物。综上所述，我们的结果表明，COL11A1赋予卵巢癌顺铂耐药性的新机制。我们的研究还发现，IAPs可作为降低卵巢癌，尤其是表达高水平COL11A1的复发性卵巢癌的顺铂耐药性的有希望的治疗靶标。在卵巢癌细胞和异种移植小鼠模型中，当COL11A1存在时，BIRC3和BIRC3足以恢复顺铂诱导的卵巢癌细胞凋亡。我们还显示，COL11A1-整合素α1β1/ DDR2- Src-PI3K / Akt-NF-kB-IAP信号通路的成分在卵巢癌患者中作为不良的预后标志物。两者合计，我们的结果表明，COL11A1赋予卵巢癌顺铂耐药性的新机制。我们的研究还发现，IAPs可作为降低卵巢癌，尤其是表达高水平COL11A1的复发性卵巢癌的顺铂耐药性的有希望的治疗靶标。在卵巢癌细胞和异种移植小鼠模型中，当COL11A1存在时，BIRC3和BIRC3足以恢复顺铂诱导的卵巢癌细胞凋亡。我们还显示，COL11A1-整合素α1β1/ DDR2- Src-PI3K / Akt-NF-kB-IAP信号通路的成分在卵巢癌患者中作为不良的预后标志物。综上所述，我们的结果表明，COL11A1赋予卵巢癌顺铂耐药性的新机制。我们的研究还发现，IAPs可作为降低卵巢癌，尤其是表达高水平COL11A1的复发性卵巢癌的顺铂耐药性的有希望的治疗靶标。我们还显示，COL11A1-整合素α1β1/ DDR2- Src-PI3K / Akt-NF-kB-IAP信号通路的成分在卵巢癌患者中作为不良的预后标志物。综上所述，我们的结果表明，COL11A1赋予卵巢癌顺铂耐药性的新机制。我们的研究还发现，IAPs可作为降低卵巢癌，尤其是表达高水平COL11A1的复发性卵巢癌的顺铂耐药性的有希望的治疗靶标。我们还显示，COL11A1-整合素α1β1/ DDR2- Src-PI3K / Akt-NF-kB-IAP信号通路的成分在卵巢癌患者中作为不良的预后标志物。综上所述，我们的结果表明，COL11A1赋予卵巢癌顺铂耐药性的新机制。我们的研究还发现，IAPs可作为降低卵巢癌，尤其是表达高水平COL11A1的复发性卵巢癌的顺铂耐药性的有希望的治疗靶标。