Abstract #4601: Phosphorylation and degradation of Mcl-1 in vinblastine-induced apoptosis

Microtubule inhibitors such as vinblastine are important anticancer drugs that inhibit the dynamics of microtubules, arrest cells in M phase, and induce subsequent apoptosis. Apoptosis is regulated by Bcl-2 family proteins including the anti-apoptotic protein Mcl-1. Mcl-1 is an important survival factor for many cancers and the expression of Mcl-1 is related to chemo-resistance. In this study, we investigated the role of Mcl-1 in vinblastine-induced apoptosis in KB-3 cells. Vinblastine and other microtubule inhibitors promoted Mcl-1 phosphorylation and subsequent degradation. However, no changes in Mcl-1 phosphorylation or expression were observed when cells were treated with lethal concentrations of DNA-damaging agents, doxorubicin or VP-16, suggesting that these modifications are specific responses to microtubule damage. The degradation of Mcl-1 was inhibited by the proteosome inhibitor MG-132. The phosphorylation of Mcl-1 in synchronized cells was inhibited by treatment with different CDK inhibitors including roscovitine, purvalanol A and RO-3306. These results suggest that CDK-dependent phosphorylation and degradation of Mcl-1 may be an important regulatory mechanism in microtubule inhibitor-induced apoptosis. Supported by NIH CA109821.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4601.