Inhibition of Akt phosphorylation attenuates resistance to TNF-α cytotoxic effects in MCF-7 cells, but not in their doxorubicin resistant derivatives

Document Type: Original Article

Authors

1 Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Pharmaceutical Research Center, Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Acquisition of TNF-α resistance plays role in the onset and growth of malignant tumors. Previous studies have demonstrated that MCF-7 cell line and its doxorubicin resistant variant MCF-7/Adr are resistant against the cytotoxic effects of TNF-α. In this study, we investigated the role of Akt activation in resistance of MCF-7 and MCF-7/Adr against TNF-α cytotoxicity.
Materials and Methods: The role of Akt activation in TNF-α cytotoxicity was investigated by MTT cell viability assay following treatment of the cells with the chemical inhibitor of Akt activation with or without TNF-α treatment. Phosphorylation of Akt at Ser473 before and after 72 hr TNF-α treatment  was also determined by western blot.
Results: TNF-α treatment led to enhancement of Akt Ser473 phosphorylation. Treatment of MCF-7 cells with TNF-α along with Akt-inhibitor agent, tricribine, attenuated Akt Ser473 phosphorylation and sensitized these cells to the cytotoxic effects of TNF-α in a dose and time dependent manner while tricribine treatment did not cause any significant cytotoxicity in MCF-7/Adr cells alone or in combination with TNF-α.
Conclusion: These results demonstrate that Akt phosphorylation plays pivotal role in the resistance of MCF-7 cells against TNF-α-induced cytotoxicity while it might play no significant role in the resistance of MCF-7/Adr cells against TNF-α.

Keywords


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