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

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.

The role of collagen in cancer: from bench to bedside

“…Nevertheless, DDR2 activated by collagen was not conducive to Src homolog 2 domain phosphorylation [48]. Notably, the binding of COL11A1 to both α1β1 integrin and DDR2 to activate the Src-phosphatidylinositol 3-kinase (PI3K)/AKT-NFκB signaling pathways induced the expression of three cisplatin-induced apoptosis inhibitors in ovarian cancer [49].…”

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

“…Cancer cells were serum starved overnight prior to the experiments. Tissue culture plates were coated with 5 µg/ ml of type I collagen (COL1; Gibco Life Technologies) or COL11A1 extracted from A204-scrambled cells or A204 shCOL11A1 cells 31 (Fig. S1B) for 2 h at 37°C.…”

“…Cancer cells were trypsinized, resuspended in 1% FBS containing medium and cultured in collagen-coated plates for 72 h before the analysis. For co-culture, CAFs were seeded in 6-well inserts (Falcon #353090) and ovarian cancer cells were plated in the companion 6-well plates (Falcon #353502) in media supplemented with 1% FBS for 72 h. CAFs have been shown to express high levels of COL11A1 and co-culture with these CAFs increased cisplatin resistance in ovarian cancer cell lines 25,27,31 . For drug treatments, cancer cells were serum starved and plated on COL11A1 extract for 48 h in media containing 1% FBS and treated with drugs (dasatinib, LY294002, MK2206 and dorsomorphin) for another 48 h. For cisplatin treatment, cancer cells were serum starved and cultured on uncoated plates, COL11A1-positive extract or COL11A1-negative extract in media containing 1% FBS for 24 h and treated with cisplatin for another 72 h.…”

“…COL11A1 is expressed and secreted by a subset of cancer-associated fibroblasts (CAFs) adjacent to tumor cells and a small number of cancer cells including A2780cis cisplatin-resistant ovarian cancer cell line [25][26][27]30 . We have previously shown that COL11A1 confers cisplatin resistance by engaging α1β1 integrin and Discoidin domain receptor 2 (DDR2) on ovarian cancer cells to activate c-Src-Akt-NFkB signaling to induce inhibitor of apoptosis proteins (IAPs) 31 . Here, we report another mechanism by which COL11A1 confers cisplatin resistance by regulating ovarian cancer cell metabolism.…”

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

“…Overexpression of DDR2 is associated with breast cancer recurrence through activation of the Erk/Snail 2 pathway (Ren et al 2013, 2). In a recent study, binding of collagen 1A to integrins and DDR2 was shown to activate the Src-PI3K/Akt-NFκB signaling pathway, allowing the expression of apoptosisinhibiting proteins (Rada et al 2018). Thus, cisplatin-induced apoptosis was shown to be inhibited in ovarian cancer cells in vitro and in vivo (Rada et al 2018).…”