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Apoptosis

, Volume 16, Issue 2, pp 174–183 | Cite as

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

  • Hsien-Chia Juan
  • Hsin-Ting Tsai
  • Po-Hao Chang
  • Chi-Ying F. Huang
  • Cheng-Po Hu
  • Fen-Hwa WongEmail author
Original Paper

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.

Keywords

Insulin-like growth factor 1 (IGF-1) 5-fluorouracil (5-Fu) Survivin Apoptosis Esophageal carcinoma 

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hsien-Chia Juan
    • 1
  • Hsin-Ting Tsai
    • 1
  • Po-Hao Chang
    • 2
  • Chi-Ying F. Huang
    • 3
  • Cheng-Po Hu
    • 4
  • Fen-Hwa Wong
    • 2
    Email author
  1. 1.Institute of Public HealthNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Department of Life Sciences and Institute of Genome SciencesNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Institute of Clinical MedicineNational Yang-Ming UniversityTaipeiTaiwan
  4. 4.Department of Life SciencesTunghai UniversityTaichungTaiwan

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