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

Abstract

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 MCF10A. We found that the proteasome inhibitor MG132 induced G1/S arrest in MCF10A, but G2/M arrest in MCF7 cells. The effect of MG132 on MCF7 was reproduced on MCF10A cells in the presence of the glycogen synthase kinase 3β (GSK-3β) inhibitor VII. Similarly, MCF7 cells overexpressing constitutively active GSK-3β behaved like MCF10A cells. On the other hand, MCF10A cells remained arrested after MG132 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-3β 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.

Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicin-induced apoptosis

“…Because studies have proposed induction of autophagy as a resistance mechanism to proteasome inhibitor treatment in breast cancer cells 31 32 , we performed immunoblotting analysis to determine how MLN9708 treatment affects the autophagy machinery. Cells were treated with MLN9708 (0.1 μM) for 24 h and then were incubated with drug-free medium for 24 h, 48 h, or 72 h. The results show that MLN9708 induced autophagy marker LC3A/B-I/II expression in the cell lines tested ( Fig.…”

GABABR/GSK‐3β/NF‐κB signaling pathway regulates the proliferation of colorectal cancer cells

“…Recent report had been reported that it can regulate the proliferation of human ovarian cancer cells in vitro (SKOV3 and ES‐2 cells) as well as in vivo . Study also showed that the relevance of GSK‐3 β as a target for controlling cell cycle progression and proliferative capacity in MCF7, highlighted the cotreatment of breast cancer . However, the deep molecular mechanism of the regulation by GSK‐3 β on CRC and its signaling pathway worths further investigation.…”

Proteasome inhibitors attenuated cholesterol-induced cardiac hypertrophy in H9c2 cells

“…In addition, the proportion of G0/G1 phase cells returned to control levels in response to 50 nM MG132 or 50 nM Bortezomib. Although we did not examine the expression level of cyclins or CDK, proteasome inhibitors may result in the changes of protein level of cyclins and CDK to inhibit degradation by proteasome as shown in previous reports (34 , 35) .…”