3‑Bromopyruvate sensitizes human breast cancer cells to TRAIL‑induced apoptosis via the phosphorylated AMPK‑mediated upregulation of DR5

Abstract

Previous studies have indicated that the sensitivity of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is associated with the expression of death receptors on the cell membrane. However, drug resistance limits the use of TRAIL in cancer therapy. Numerous studies have indicated that death receptors, which induce apoptosis, are upregulated by the endoplasmic reticulum (ER) stress response. 3-Bromopyruvate (3-BP), an anticancer agent, inhibits cell growth and induces apoptosis through interfering with glycolysis. In the present study, it was demonstrated that 3-BP synergistically sensitized breast cancer cells to TRAIL-induced apoptosis via the upregulation of death receptor 5 (DR5). Furthermore, we found that the protein levels of glucose-related protein 78 (GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP) increased following treatment with 3-BP. The expression of Bax (in MCF-7 cells) and caspase-3 (in MDA-MB-231 cells) increased following co-treatment with 3-BP and TRAIL, whereas the expression of the anti-apoptotic protein Bcl-2 decreased. In order to investigate the molecular mechanism regulating this effect, the expression of adenosine monophosphate-activated protein kinase (AMPK), activated by 3-BP, was determined. It was demonstrated that phosphorylated-AMPK was upregulated following treatment with 3-BP. Notably, Compound C, an AMPK inhibitor, reversed the effects of 3-BP. Finally, a synergistic antitumor effect of 3-BP and TRAIL was observed in MCF-7 cell xenografts in nude mice. In conclusion, these results indicated that 3-BP sensitized breast cancer cells to TRAIL via the AMPK-mediated upregulation of DR5.

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

“…Using 3-BrPA as a sensitizer to target glycolysis of breast cancer cells, the antitumor effects of tamoxifen were markedly improved through multiple modulation in apoptosis, angiogenesis, oxidative stress, and metastatic potential in vitro and in vivo [61]. In addition, 3-BrPA sensitized human breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via the p-AMPK-mediated upregulation of death receptor 5 (DR5) [106], similar to the mechanism described in a previous study [86]. In mice tumor xenograft of MCF-7 cells, drug treatments resulted in a typical necrotic area within tumors, a synergistic antitumor effect of 3-BrPA and TRAIL was observed without evident hepatotoxicity and nephrotoxicity as well [106].…”

3-Bromopyruvate potentiates TRAIL-induced apoptosis in human colon cancer cells through a reactive oxygen species- and caspase-dependent mitochondrial pathway

“…The present study showed for the first time that 3-BP enhanced TRAIL-induced apoptosis in colon cancer cells. Previous studies have demonstrated that 3-BP sensitizes nasopharyngeal and breast cancer cells to TRAIL (Can et al 2017;Chen et al 2018). In this study TRAIL alone had no significant antiproliferative effect on colon cancer cells.…”

“…3-Bromopyruvate (3-BP) as a hexokinase II inhibitor has shown to induce cell death in colon cancer cells (HT-29 ) through a variety of different mechanisms (Ko et al 2004;Tang et al 2012). Two previous studies have demonstrated that 3-BP enhances TRAIL-induced apoptosis in nasopharyngeal and breast cancer cells (Can et al 2017;Chen et al 2018). It has not been examined whether co-treatment of 3-BP and TRAIL D r a f t can attenuate TRAIL resistance in colon cancer cells.…”

AMPK Activation of Apoptotic Markers in Human Breast Cancer Cell Lines with Different p53 Backgrounds: MCF-7, MDA-MB-231 and T47D Cells

“…Bax translocation was increased by prolonged incubation with AICAR, except in MCF-7 cells (Figure 2); this might have contributed to the acquired resistance of this cell line to the anti-proliferative effect of AICAR at high concentrations reported earlier (El-Masry et al, 2012). In addition, 3-Bromopyruvateactivated AMPK resulted in increasing the expression of Bax in MCF-7 and caspase 3 in MDA-MB-231 cells to support TRAIL-stimulated apoptotic mechanisms (Chen et al, 2018). According to another study (Okoshi et al, 2008), phosphorylation of Ser46 was also associated with AMPK-mediated apoptosis in response to energy stresses, which suggests that the presence of functional p53 is required for the pro-apoptotic influence of AMPK.…”