Abstract B22: Inhibition of the coding region determinant-binding protein (CRD-BP) to sensitize colorectal cancer cells to drug

Abstract

Abstract This study aims at targeting CRD-BP to sensitize colorectal cancer cells to chemotherapeutics. Colorectal cancer is the third most common cancer in both men and women. An estimated 95,270 cases of colon cancer and 39,220 cases of rectal cancer are expected to be diagnosed in 2016. Treatment for colorectal cancer may involve surgery, chemotherapy, biological therapy, radiation therapy, or a combination of treatments. The choice of treatment of colorectal cancer depends mainly on the location of the tumor and the stage of the disease. Chemotherapy is used for advanced cancers; however advanced colorectal cancers are notoriously resistant to drugs. Two major mechanisms employed by colorectal cancer cells are thought to be responsible for insensitivity to therapeutics: i) resistance to apoptosis usually achieved by activation of anti-apoptotic pathways; ii) induction of multidrug resistance (MDR) membrane transporters that pump drugs out of the cells. Targeting factors involved in these mechanisms would overcome the resistance of colorectal cancer cells to drugs. Constitutive activation of the Wnt/β-catenin signaling pathway is one of the central drivers of the development of colorectal cancer. We have identified CRD-BP as a bona fide transcriptional target of Wnt/β-catenin signaling pathway. Induction of CRD-BP is responsible for a variety of pleiotropic effects of Wnt/β-catenin signaling pathway in human colorectal cancer cells such as up-regulation of c-myc and β-TrCP1, activation of NF-κB pathways via accelerated degradation of IκB, and inhibition of apoptosis. More over CRD-BP was shown to regulate the multidrug resistance-1 (MDR-1) membrane transporter which is responsible for the resistance to a large variety of drugs in human cells. This makes CRD-BP an attractive target for sensitization of colorectal cancer cells to chemotherapeutics. To assess the effects of CRD-BP inhibition on the sensitivity of colorectal cancer cells to chemotherapeutics, we used colorectal cancer cell lines with different status of activation of Wnt signaling pathway, and different degrees of aggressiveness. A normal epithelial colon cell line served as control in our study. Our results show that in colorectal cancer cells with activated Wnt signaling, CRD-BP inhibition potentiates their anti-growth response to chemotherapeutics. This study may potentially lead to design of the agents capable of inhibiting both cell proliferation and drug efflux from the cells. This would be more effective in the treatment of colorectal cancer. Chemotherapeutic drugs are known for their notorious side effects. This study might help in the long run in reducing the dose of chemotherapeutic agents and in lessening the side effects of treatment. This would significantly improve the management of the disease. Citation Format: Felicite Noubissi, Vladimir Spiegelman. Inhibition of the coding region determinant-binding protein (CRD-BP) to sensitize colorectal cancer cells to drug. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B22.