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P-glycoprotein enhances radiation-induced apoptotic cell death through the regulation of miR-16 and Bcl-2 expressions in hepatocellular carcinoma cells

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Abstract

P-glycoprotein (Pgp), an efflux pump, was confirmed the first time to regulate the expressions of miR/gene in cells. Pgp is known to be associated with multidrug resistance. RHepG2 cells, the multidrug resistant subline of human hepatocellular carcinoma HepG2 cells, expressed higher levels of Pgp as well as miR-16, and lower level of Bcl-2 than the parental cells. In addition, RHepG2 cells were more radiation sensitive and showed more pronounced radiation-induced apoptotic cell death than the parental cells. Mechanistic analysis revealed that transfection with mdr1 specific antisense oligos suppressed radiation-induced apoptosis in HepG2 cells. On the other hand, ectopic mdr1 expression enhanced radiation-induced apoptosis in HepG2 cells, SK-HEP-1 cells, MiHa cells, and furthermore, induced miR-16 and suppressed its target gene Bcl-2 in HepG2 cells. Moreover, the enhancement effects of Pgp and miR-16 on radiation-induced apoptosis were counteracted by overexpression of Bcl-2. The Pgp effect on miR-16/Bcl-2 was suppressed by Pgp blocker verapamil indicating the importance of the efflux of Pgp substrates. The present study is the first to reveal the role of Pgp in regulation of miRNA/gene expressions. The findings may provide new perspective in understanding the biological function of Pgp.

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Acknowledgments

The pHaMDR plasmid was a gift from Dr. Michael Gottesman, Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH. This work was supported by the General Research Fund (CUHK466908, CUHK467609) from Hong Kong Research Grants Council.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China

    Tsun Yee Tsang, Judy Yuet Wa Chan, Ngai Na Co, Chi Lam Au Yeung, Pak Lun Yau, Kwok Pui Fung & Tim Tak Kwok

  2. Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH, USA

    Wan Yee Tang

  3. School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China

    Siu Kai Kong

  4. School of Biomedical Sciences, The Chinese University of Hong Kong, Rm 190B, Science Center Southern Block, Shatin, Hong Kong SAR, China

    Tsun Yee Tsang

  5. School of Biomedical Sciences, The Chinese University of Hong Kong, Rm 177, Science Center Southern Block, Shatin, Hong Kong SAR, China

    Tim Tak Kwok

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  1. Tsun Yee Tsang
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Correspondence to Tsun Yee Tsang or Tim Tak Kwok.

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Tsang, T.Y., Tang, W.Y., Chan, J.Y.W. et al. P-glycoprotein enhances radiation-induced apoptotic cell death through the regulation of miR-16 and Bcl-2 expressions in hepatocellular carcinoma cells. Apoptosis 16, 524–535 (2011). https://doi.org/10.1007/s10495-011-0581-5

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