Abstract B28: The stress phenotype makes ovarian cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

Abstract

Abstract CDT2/L2DTL/RAMP is one of the substrate receptors that binds the CRL4 ubiquitin ligase and confers it specificity for a number of substrates, such as CDT1, p21 and CHK1. Previously, we reported that in ovarian cancer cell lines increased susceptibility to cisplatin is associated to the down-regulation of the CDT2 gene. Here we show that CDT2 depletion was alone able to induce the apoptotic death not only in ovarian cancer cell lines but also in 10/10 other human cancer cell lines from different tissues, irrespective of p53, ATM and ATR status and CDT2 expression level. Conversely, CDT2 depletion did not affect non-transformed human cells, such as immortalized kidney, lung and breast cell lines, and primary cultures of endothelial cells and osteoblasts. After CDT2 suppression, all cancer cells underwent rereplication associated to the inability to destroy CDT1 and to cell death. The ectopic over-expression of an activated oncogene, such as the mutation-activated RAS or the amplified MET in non-transformed immortalized breast cell lines and primary human osteoblasts, respectively, made cells transformed in vitro, tumorigenic in vivo, and susceptible to CDT2 loss. Conversely, the knock-down of the tumor suppressor genes PTEN or RB1 did not transform immortalized breast cells and did not sensitize them to CDT2 loss. These data show that transformation makes cells “addicted” to CDT2. The widespread effect of CDT2 depletion in different cancer cells suggests that CDT2 is not in a synthetic lethal interaction to another specific gene or pathway but becomes dominant in these cells because of their stress phenotype, due to DNA damage, replication and mitotic stress. Citation Format: Martina Olivero, Daniela Dettori, Sabrina Arena, Davide Zecchin, Erica Lantelme, Maria Flavia Di Renzo. The stress phenotype makes ovarian cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B28.