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.

• Authors: Yuzhong Chen, Li Wei, Xiaojing Zhang, Xianfu Liu, Yansong Chen, Song Zhang, Lanzhu Zhou, Qixiang Li, Qiong Pan, Surong Zhao, Hao Liu
• Journal: Oncology reports (Oncol Rep) Vol. 40 Issue 5 Pg. 2435-2444 (Nov 2018) ISSN: 1791-2431 [Electronic] Greece
• PMID: 30132536 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Hspa5 protein, mouse
• Pyrazoles
• Pyrimidines
• Pyruvates
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Recombinant Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10B protein, human
• TNFSF10 protein, human
• dorsomorphin
• bromopyruvate
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylation
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Pyruvates (pharmacology, therapeutic use)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Recombinant Proteins (pharmacology, therapeutic use)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology, therapeutic use)
• Up-Regulation
• Xenograft Model Antitumor Assays