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Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol

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Abstract

We have investigated the interrelationship between two anti-apoptotic factors, XIAP and Akt, and their role in chemoresistance of uterine cancer cells. We used one cervical cancer cell line (HeLa) and two endometrial cancer cell lines (KLE and Ishikawa) as a model. The three drugs decreased Akt and XIAP content and induced apoptosis in P-Akt-negative HeLa cells. In P-Akt1/3-positive Ishikawa cells apoptosis induction correlated with XIAP decrease. P-Akt1/2/3-positive KLE cells showed maximum chemoresistance as XIAP and Akt levels/phosphorylation remained stable in response to the three drugs, and only cisplatin could significantly induce apoptosis. We found that XIAP and Akt were functionally linked in uterine cancer cells, as downregulation of XIAP with RNAi decreased P-Akt levels, and inhibition of PI3-K/Akt activity using LY294002 decreased XIAP content. Overexpression of constitutively active Akt isoforms in HeLa cells induced isoform-specific sensitivity to doxorubicin and taxol but not cisplatin. XIAP RNAi increased the cell-specific sensitivity to cisplatin and doxorubicin but not taxol. Finally, we found P-Akt immunoreactivity in epithelial cells from multiple human endometrial carcinoma tumors, suggesting that Akt may also regulate chemosensitivity in uterine cancers in vivo. Altogether these results highlight an intertwined role for specific Akt isoforms and XIAP in chemoresistance of uterine cancer cells.

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Acknowledgements

The authors want to thank Mrs. Sophie Parent for technical assistance. This work has been supported by a grant from CIHR (MOP-66987). Eric Asselin is holder of a New Investigator award of the Canadian Institute of Health Research of Canada (CIHR) and Chairholder of the Canada Research Chair in Molecular Gyneco-Oncology.

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Authors and Affiliations

  1. Department of Chemistry and Biology, Medical Biology Section, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, QC, Canada, G9A 5H7

    Véronique Gagnon, Céline Van Themsche, Steve Turner, Valérie Leblanc & Eric Asselin

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  1. Véronique Gagnon
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  2. Céline Van Themsche
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  3. Steve Turner
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  4. Valérie Leblanc
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  5. Eric Asselin
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Correspondence to Eric Asselin.

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Gagnon, V., Van Themsche, C., Turner, S. et al. Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol. Apoptosis 13, 259–271 (2008). https://doi.org/10.1007/s10495-007-0165-6

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  • DOI: https://doi.org/10.1007/s10495-007-0165-6

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