Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest.

c-Jun is a major component of the AP-1 transcription factor and plays a key role in regulation of diverse biological processes including proliferation and apoptosis. Treatment of a wide variety of cells with the microtubule inhibitor vinblastine leads to a robust increase in c-Jun expression, JNK-mediated c-Jun phosphorylation, and activation of AP-1-dependent transcription. However, the role of c-Jun induction in the response of cells to vinblastine remains obscure. In this study we used MCF7 breast cancer cell lines that express the dominant-negative form of c-Jun, TAM-67, as well as cells that overexpress c-Jun, under the control of an inducible promoter. Vinblastine induced c-Jun protein expression, c-Jun phosphorylation, and AP-1 activation in MCF7 cells, and these parameters were strongly inhibited by inducible TAM-67 expression and strongly enhanced by inducible c-Jun expression. Vinblastine-induced cell death was not affected by TAM-67 expression whereas cells were protected by c-Jun overexpression. Further investigation revealed that apoptotic and senescent cells were observed after vinblastine treatment and that both outcomes were strongly inhibited by c-Jun overexpression. Although c-Jun expression inhibited cell death, it did not affect the ability of vinblastine to induce mitotic arrest. These results indicate that c-Jun expression plays a protective role in the cellular response to vinblastine and operates post-mitotic block to inhibit drug-induced apoptosis and senescence.

Citation

Lingling Duan, Kristen Sterba, Sergey Kolomeichuk, Heetae Kim, Powel H Brown, Timothy C Chambers. Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest. Biochemical pharmacology. 2007 Feb 15;73(4):481-90

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PMID: 17126817

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