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Tumor Biology

, Volume 34, Issue 2, pp 683–693 | Cite as

Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells

  • Zhen-Yu Ding
  • Gui-Hong Liu
  • Birgit Olsson
  • Xiao-Feng Sun
Research Article

Abstract

The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. However, there are only limited reports regarding its expression and biological functions in colon cancer. Here, we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C, and SW620) in the presence or absence of cisplatin that was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was upregulated after cisplatin treatment in a dose-dependent manner. Both immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, cisplatin treatment activated the mammalian target of rapamycin (mTOR) pathway as shown by increased phosphorylation of Akt1, mTOR, S6K, and 4E-BP1, together with the elevated Livin. The PI3K inhibitor LY294002 inhibited both the phosphorylation of mTOR and upregulation of Livin. The stable overexpression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin, while the knockdown of Livin by siRNA rendered colon cancer cells more sensitive to cisplatin. Our study, along with others, highlighted the potential of Livin for cancer therapy in colon cancer.

Keywords

Livin Apoptosis Cisplatin Colon cancer 

Notes

Acknowledgments

We thank Prof. IJ Fidler from Anderson Cancer Center for his generosity of providing the KM12C cells, Dr. Chun Wang for the statistical analysis, and Dr. David Hinselwood for linguistic revision of the manuscript. This study was supported by grants from the National Natural Science Fund of China (30901756), Doctoral Fund of Ministry of Education of China (20090181120100), Swedish Cancer Foundation, Swedish Research Council, and the Health Research Council in the South-East of Sweden.

Conflicts of interest

None.

Supplementary material

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Online Resource 1

Different responses to cisplatin in colon cancer cells. a Colon cancer cells (HCT116, RKO, KM12C, and SW620) were treated with cisplatin at the concentration of 10 μg/ml or 20 μg/ml for 24 or 48 h. The cell viability was determined by trypan blue exclusion and viable cells were counted on an automatic cell counter. b The cells were treated with cisplatin (1 μg/ml) for 6 h and seeded to six-well plate, 500 cells each well. Seven to ten days later, the colonies were stained with Giemsa and observed under the microscope. c The colony numbers were recorded for each cell line (JPEG 25 kb)

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Online Resource 2

Caspase-3 activation in cisplatin-treated colon cancer cells. RKO and SW620 cells were treated with increasing concentration of cisplatin (1, 5, 10, and 20 μg/ml) for 24 h. The lysates were detected for caspase-3 activity in the kinetic mode where the data were collected every 30 min (JPEG 11 kb)

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Livin-transfected HCT-116 cells became resistant to oxaliplatin than vector-treated ones (JPEG 3 kb)

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All 8 colon cancer cell lines had Livin expression as detected by Western blot (JPEG 3 kb)

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High resolution image (TIFF 165 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Zhen-Yu Ding
    • 1
    • 2
  • Gui-Hong Liu
    • 2
  • Birgit Olsson
    • 1
  • Xiao-Feng Sun
    • 1
  1. 1.Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Country Council of ÖstergötlandUniversity of LinköpingLinköpingSweden
  2. 2.Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical SchoolSichuan UniversityChengduChina

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