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Insulin-like growth factor 1 mediates 5-fluorouracil chemoresistance in esophageal carcinoma cells through increasing survivin stability

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Abstract

Insulin-like growth factor 1 (IGF-1) inhibits 5-fluorouracil (5-Fu)-induced apoptosis in esophageal carcinoma cells; however, the mechanisms for IGF-1-induced 5-Fu chemoresistance remain unknown. In the human esophageal carcinoma cell line, CE48T/VGH, we show that IGF-1 up-regulated survivin expression at the post-transcriptional level and this up-regulation is mediated by both the PI3-K/Akt and casein kinase 2 signaling pathways. We then examine whether IGF-1-induced 5-Fu chemoresistance is mediated through up-regulation of survivin. Ectopic expression of survivin inhibits 5-Fu-induced apoptosis; furthermore, the abolition of survivin expression sensitizes cells to 5-Fu treatment and prevents the anti-apoptotic function of IGF-1 in esophageal carcinoma cell lines. We also found that ectopic expression of survivin or treatment with IGF-1 inhibits the release of Smac/DIABLO and caspases activation after 5-Fu treatment. Our results strongly suggest that IGF-1 inhibits 5-Fu induced apoptosis through increasing survivin levels, which prevents Smac/DIABLO release and blocks the activation of caspases. Therefore, up-regulation of IGF-1 and survivin would seem to be responsible for 5-Fu chemoresistance in esophageal cancer patients and these factors may be the valuable predictors of 5-Fu chemoresistance in esophageal carcinoma.

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Acknowledgments

This work was supported in part by grants from the National Science Council (NSC93-3112-B-010-026; NSC94-3112-B-010-012; NSC95-3112-B-010-003) and Ministry of Education, Aim for the Top University Plan (95A-C-T04-56; 96A-D-T137; 98A-C-D127) to F-H. Wong. We are grateful to Dr. Chen-Kung Chou (Graduate Institute of Basic Medical Science, Chang-Gung University, Taiwan) for helpful comments on the manuscript. We thank Dr. Michael Hsiao (Genomic Research Center of Academia Sinica, Taiwan) for the Ad-Akt-DN vector and the VGH National Yang-Ming University Genome Research Center (YMGC) for pOTB7-Smac plasmid.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Public Health, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 11221, Taiwan

    Hsien-Chia Juan & Hsin-Ting Tsai

  2. Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 11221, Taiwan

    Po-Hao Chang & Fen-Hwa Wong

  3. Institute of Clinical Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 11221, Taiwan

    Chi-Ying F. Huang

  4. Department of Life Sciences, Tunghai University, No.181, Sec.3, Taichung Port Road, Taichung, 40704, Taiwan

    Cheng-Po Hu

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  1. Hsien-Chia Juan
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Correspondence to Fen-Hwa Wong.

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Juan, HC., Tsai, HT., Chang, PH. et al. Insulin-like growth factor 1 mediates 5-fluorouracil chemoresistance in esophageal carcinoma cells through increasing survivin stability. Apoptosis 16, 174–183 (2011). https://doi.org/10.1007/s10495-010-0555-z

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