Platinum-based chemotherapy has been used for more than four decades for ovarian cancer patients. Although initially most ovarian tumors respond well to cisplatin treatment, many of the tumors become resistant to chemotherapy. Several drug resistant-associated genes have been identified by gene expression arrays in drug sensitive and drug resistant cells. Recent evidence indicates that posttranscriptional and posttranslational regulation of gene expression governs the function of several proteins associated with cancer initiation, progression and drug resistance. To reveal additional proteins associated with cisplatin resistance, we performed a proteomic analysis in cisplatin sensitive (A2780) and cisplatin resistant (A2780CP20) ovarian cancer cells. Forty-seven, out of 148 identified proteins, were differentially abundant in A2780CP20 compared with A2780 cancer cells. Western blot analysis was used to confirm the proteomic results. Particularly, the Integrin-Linked Kinase-Associated Serine/Threonine Phosphatase 2C (ILKAP) was decreased in A2780CP20 compared with A2780 cells. The phosphorylation levels of the Integrated-Linked Kinase ILK (the major ILKAP effector), protein kinase B (AKT), and glycogen synthase kinase 3β (GSK3β) (two ILK downstream effectors) were higher in A2780CP20 compared with A2780 cells. Small-interference RNA (siRNA)-targeted ILK, reduced the phosphorylation levels of AKT and GSK3β; and reduced cell proliferation and invasion of the A2780CP20 cells. Most important, combination of inactive ILK-targeted siRNA doses plus inactive cisplatin doses reduced cell growth in a synergistic-like way. These results indicate that protein phosphorylation of the ILK/AKT/GSK3β cascade play a vital role in cisplatin resistance, and propose ILK as a therapeutic target for advanced and drug resistant ovarian cancer.
Citation Format: Daniel Soto, Fatima Valiyeva, Ileabett Echevarria, Jeyshka Reyes, Pablo E. Vivas-Mejia. Integrin-linked kinase and proximal signaling contributes to the cisplatin resistance of ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3454. doi:10.1158/1538-7445.AM2014-3454