Inhibition of Akt phosphorylation attenuates resistance to TNF-α cytotoxic effects in MCF-۷ cells, but not in their doxorubicin resistant derivatives

Objective(s): Acquisition of TNF-α resistance plays role in the onset and growth of malignant tumors. Previous studies have demonstrated that MCF-۷ cell line and its doxorubicin resistant variant MCF-۷/Adr are resistant against the cytotoxic effects of TNF-α. In this study, we investigated the role of Akt activation in resistance of MCF-۷ and MCF-۷/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 Ser۴۷۳ before and after ۷۲ hr TNF-α treatment  was also determined by western blot. Results: TNF-α treatment led to enhancement of Akt Ser۴۷۳ phosphorylation. Treatment of MCF-۷ cells with TNF-α along with Akt-inhibitor agent, tricribine, attenuated Akt Ser۴۷۳ 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-۷/Adr cells alone or in combination with TNF-α. Conclusion: These results demonstrate that Akt phosphorylation plays pivotal role in the resistance of MCF-۷ cells against TNF-α-induced cytotoxicity while it might play no significant role in the resistance of MCF-۷/Adr cells against TNF-α.

Keywords:

Akt , Breast carcinoma , Multidrug resistance , Protein kinase B , Tumor necrosis factor-alpha