Inhibition of NANOG/NANOGP8 Downregulates MCL-1 in Colorectal Cancer Cells and Enhances the Therapeutic Efficacy of BH3 Mimetics

摘要: Purpose: High levels of BCL-2 family members in colorectal carcinoma cause resistance to treatment. Inhibition NANOG or its paralog NANOGP8 reduces the proliferation, stemness, and tumorigenicity cells. Our hypothesis was that inhibition NANOG/NANOGP8 enhances cytotoxic effect BH3 mimetics targeting cells through reducing expression MCL-1, a prosurvival protein. Experimental Design: Lentiviral vector (LV) shRNA (shNG-1) (shNp8-1) transduced were also exposed ABT-737 ABT-199 vivo xenografts vitro where protein gene expression, apoptosis measured. Results: Clone A CX-1 sensitive at IC 50s 2 9 μmol/L but LS174T resistant with 18 30 μmol/L. Resistance associated high MCL-1 LS174T. LVshNG-1 LVshNp8-1 decreased increased apoptosis, replating efficiency treated either compared effects mimetic alone. overexpression alone replicated increasing decreasing caused mimetic. The combination therapy inhibited growth untreated controls treatment only LV ABT-737. Conclusions: cytotoxicity target members. Gene NANOGs may increase efficacy carcinoma. Clin Cancer Res; 20(21); 5446–55. ©2014 AACR .