About this item:

351 Views | 366 Downloads

Author Notes:

Correspondence: wangquan-jlcc@hotmail.com

Authors’ contributions- QW and ABC designed the study; QW, FW, CL, KZ and ACB performed the experiments; QW and FW analyzed and interpreted the results; GL, TL and CH contributed materials. ACB and CH wrote the manuscript. CGH edited and revised the manuscript. All authors read and approved the final manuscript.

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.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

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:

  • Apoptosis
  • Colorectal carcinoma
  • ERK
  • IGF-1R
  • IGF-1R inhibitor
  • TP53

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

Tools:

Journal Title:

BMC Cancer

Volume:

Volume 13

Publisher:

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2013 Wang et al.; licensee BioMed Central Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/).

Creative Commons License

Export to EndNote