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Brief Report

Inhibition of Paclitaxel-Induced Proteasome Activation Influences Paclitaxel Cytotoxicity in Breast Cancer Cells in a Sequence-Dependent Manner

Héctor Hernández-Vargas, Cayetano von Kobbe, Carolina Sánchez-Estévez, Mercedes Julián-Tendero, José Palacios and Gema Moreno-Bueno

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Although the anti-tumour effects of paclitaxel result mainly from mitotic arrest, recent evidences suggest alternative mechanisms of cytotoxicity. Cell cycle, cell death, and gene expression assays were used to understand the molecular mechanisms of paclitaxel cytotoxicity in breast cancer cells. G₂/M cell cycle arrest and cell death coincided with the regulation of genes involved in cell death, cell cycle control, microtubule-based processes, oxidative stress, and ubiquitin-proteasome system. Induction of proteasome genes was also correlated with an accumulation of protein for proteasome subunits. Furthermore, a schedule-dependent regulation of paclitaxel-induced cytotoxicity was observed after combining paclitaxel and the proteasome inhibitor MG132. Proteasome inhibition after paclitaxel exposure induced the highest rate of growth inhibition and apoptosis, with no effect on mitotic arrest. These findings give support to clinical combinations of taxanes with proteasome inhibitors, outlining the importance of considering the sequence when designing such regimens.

Authors

Héctor Hernández-Vargas

Spanish National Cancer Centre; Madrid, Spain

Cayetano von Kobbe

Spanish National Cancer Centre (CNIO); Madrid, Spain

Carolina Sánchez-Estévez

Spanish National Cancer Centre (CNIO); Madrid, Spain

Mercedes Julián-Tendero

Spanish National Cancer Centre (CNIO); Madrid, Spain

José Palacios

Spanish National Cancer Centre (CNIO); Madrid, Spain

Gema Moreno-Bueno

Instituto de Investigaciones Biomedicas Alberto Sols; Madrid, Spain

Purchase article for $19

Subscribe to this journal for $129/year