Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment

Abstract

Bcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2-overexpressing lung and breast cancer cells were more sensitive to both paclitaxel and vinorelbine. Bcl-2 over-expression also significantly potentiated in vivo efficacy of paclitaxel, in terms of tumor volume decrease and survival benefits, in models of nude mice bearing lung cancer xenografts. To further investigate this favorable effect of Bcl-2, a genomic approach was taken. It revealed that Bcl-2 overexpression induced up-regulation of the proapoptotic protein Bim in lung cancer cells and that, conversely, Bcl-2 silencing decreased Bim expression level. A gene regulation study implicated the transcription factor Forkhead box-containing protein, class O3a in Bim up-regulation. Lastly, we show that Bim was responsible for MTA-triggered lung cancer cell death through a dynamin-related protein 1-mediated mitochondrial fragmentation. The Bcl-2-governed Bim induction evidence offers for the first time an explanation for the favorable higher sensitivity to treatment shown by Bcl-2-overexpressing cells. We suggest that Bim could be a powerful predictive factor for tumor response to MTA chemotherapy. Our data also give new insight into some failures in the efficacy of therapies targeted against Bcl-2.

High BIM mRNA levels are associated with longer survival in advanced gastric cancer

“…Patients with low BIM mRNA levels exhibited higher mortality than those with high or intermediate BIM mRNA levels (HR, 2.61; 95% CI, 1.21-5.62; P=0.010). These results were consistent with previously published data suggesting that overexpression of BIM was accompanied by a collateral increase in sensitivity to taxanes (19), which may translate into prolonged OS.…”

“…In addition, overexpression of BIM enhanced the in vitro sensitivity to docetaxel of non-small cell lung cancer (NSCLC) (18). Consistent with this finding, downregulation of BIM by small interfering RNA (siRNA) delayed paclitaxel-mediated apoptosis, indicating that low BIM expression levels were responsible for resistance to paclitaxel (19). Notably, pre-treatment mRNA levels of BIM strongly predicted the capacity of epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and phosphoinositide 3-kinase (PI3K) inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-mutant tumors, respectively (20).…”

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

“…Normotensive sham-operated (Sham) mice underwent a similar surgical process, except without the injection of MCF-7 human breast cancer cells. The study was approved by the Ethics Committee of Zhejiang Provincial People's Hospital, Hangzhou, China Tumor size was calculated according to the following formula: Length x width x depth x 0.5236 (27).…”

Insulin Promotes Proliferation and Migration of Breast Cancer Cells through the Extracellular Regulated Kinase Pathway

“…To establish the xenograft mouse model, MCF-7 human breast cancer cells were dilute with phosphate-buffered saline (PBS) at a concentration of 5×10 7 cells/ml, and 100μl MCF-7 human breast cancer cells in PBS were injected subcutaneously into the left back armpit of each mouse (Yu et al, 2010). Tumor size was calculated according to the following formula: length × width × depth × 0.5236 (Savry et al, 2013).…”