Breast cancer cell line MCF7 escapes from G1/S arrest induced by proteasome inhibition through a GSK-3β dependent mechanism

Targeting the ubiquitin proteasome pathway has emerged as a rational approach in the treatment of human cancers. Autophagy has been described as a cytoprotective mechanism to increase tumor cell survival under stress conditions. Here, we have focused on the role of proteasome inhibition in cell cycle progression and the role of autophagy in the proliferation recovery. The study was performed in the breast cancer cell line MCF7 compared to the normal mammary cell line MCF(10)A. We found that the proteasome inhibitor MG(132) induced G(1)/S arrest in MCF(10)A, but G(2)/M arrest in MCF7 cells. The effect of MG(132) on MCF7 was reproduced on MCF(10)A cells in the presence of the glycogen synthase kinase 3 beta (GSK-3 beta) inhibitor VII. Similarly, MCF7 cells overexpressing constitutively active GSK-3 beta behaved like MCF(10)A cells. On the other hand, MCF(10)A cells remained arrested after MG(132) removal while MCF7 recovered the proliferative capacity. Importantly, this recovery was abolished in the presence of the autophagy inhibitor 3-methyladenine (3-MA). Thus, our results support the relevance of GSK-3 beta and autophagy as two targets for controlling cell cycle progression and proliferative capacity in MCF7, highlighting the co-treatment of breast cancer cells with 3-MA to synergize the effect of the proteasome inhibition.