The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin

• Type of Material: Article
• Authors: Quan Wang, First Hospital of Jilin University; Feng Wei, First Hospital of Jilin University; Guoyue Lv, First Hospital of Jilin University; Chunsheng Li, Third Hospital of Jilin University; Tongjun Liu, Third Hospital of Jilin University; Constantinos G Hadjipanayis, Emory University; Guikai Zhang, Emory University; Chunhai Hao, Emory University; Anita C Bellail, Emory University
• Language: English
• Date: 2013-11-04
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Wang et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.biomedcentral.com/1471-2407/13/521
• Title of Journal or Parent Work: BMC Cancer
• ISSN: 1471-2407
• Volume: 13
• Grant/Funding Information: This study was supported in part by NIH grant CA129687 to C. Hao.; This work was also supported by grants from the NIH NS053454, Georgia Cancer Coalition Distinguished Cancer Clinicians and Scientific Program, and the Dana Foundation to C. G. Hadjipanayis.
• Keywords: ERK; Colorectal carcinoma; Apoptosis; IGF-1R; TP53; IGF-1R inhibitor
• Research Categories: Health Sciences, Oncology; Biology, Cell

Abstract

Background: There is growing evidence indicating the insulin-like growth factor 1 receptor (IGF-1R) plays a critical role in the progression of human colorectal carcinomas. IGF-1R is an attractive drug target for the treatment of colon cancer. Picropodophyllin (PPP), of the cyclolignan family, has recently been identified as an IGF-1R inhibitor. The aim of this study is to determine the therapeutic response and mechanism after colorectal carcinoma treatment with PPP. Methods: Seven colorectal carcinoma cell lines were treated with PPP. Following treatment, cells were analyzed for growth by a cell viability assay, sub-G1 apoptosis by flow cytometry, caspase cleavage and activation of AKT and extracellular signal-regulated kinase (ERK) by western blot analysis. To examine the in vivo therapeutic efficacy of PPP, mice implanted with human colorectal carcinoma xenografts underwent PPP treatment. Results: PPP treatment blocked the phosphorylation of IGF-1R, AKT and ERK and inhibited the growth of TP53 wild-type but not mutated colorectal carcinoma cell lines. The treatment of PPP also induced apoptosis in TP53 wild-type cells as evident by the presence of sub-G1 cells and the cleavage of caspase-9, caspase-3, DNA fragmentation factor-45 (DFF45), poly (ADP-ribose) polymerase (PARP), and X-linked inhibitor of apoptosis protein (XIAP). The loss of BAD phosphorylation in the PPP-treated TP53 wild type cells further suggested that the treatment induced apoptosis through the BAD-mediated mitochondrial pathway. In contrast, PPP treatment failed to induce the phosphorylation of AKT and ERK and caspase cleavage in TP53 mutated colorectal carcinoma cell lines. Finally, PPP treatment suppressed the growth of xenografts derived from TP53 wild type but not mutated colorectal carcinoma cells. Conclusions: We report the association of TP53 mutations with the resistance of treatment of colorectal carcinoma cells in culture and in a xenograft mouse model with the IGF-1R inhibitor PPP. TP53 mutations often occur in colorectal carcinomas and could be used as a biomarker to predict the resistance of colorectal carcinomas to the treatment by this IGF-1R inhibitor.