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

BMC Cancer

Quan Wang⁴  Feng Wei⁴  Guoyue Lv⁴  Chunsheng Li¹  Tongjun Liu¹  Costas G Hadjipanayis³  Guikai Zhang²  Chunhai Hao²  Anita C Bellail² 

[1] Department of Colorectal Surgery, Third Hospital of Jilin University, Changchun, Jilin 130033, China

[2] Department of Pathology & Laboratory Medicine, Emory University, Atlanta, GA 30322, USA

[3] Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA

[4] Department of Gastrointestinal Surgery, Department of Hepatopancreatobiliary Surgery, First Hospital of Jilin University, Changchun, Jilin 130021, China

关键词: TP53;    IGF-1R inhibitor;    IGF-1R;    ERK;    Colorectal carcinoma;    Apoptosis;   

Others  :  1079472
DOI  :  10.1186/1471-2407-13-521

 received in 2013-04-24, accepted in 2013-10-31,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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