3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway

• Published in: Anti-cancer drugs Vol. 25; no. 4; p. 447
• Main Authors: Liu, Zhe, Zhang, Yuan-Yuan, Zhang, Qian-Wen, Zhao, Su-Rong, Wu, Cheng-Zhu, Cheng, Xiu, Jiang, Chen-Chen, Jiang, Zhi-Wen, Liu, Hao
• Format: Journal Article
• Language: English
• Published: England 01.04.2014
• Subjects: Antineoplastic Agents, Alkylating - pharmacology; Apoptosis - drug effects; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caspases - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chromones - pharmacology; Down-Regulation; Female; Hexokinase - antagonists & inhibitors; Humans; Morpholines - pharmacology; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Oncogene Protein v-akt - antagonists & inhibitors; Oncogene Protein v-akt - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Pyruvates - pharmacology; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; Signal Transduction
• ISSN: 1473-5741
• DOI: 10.1097/cad.0000000000000081

The hexokinase inhibitor 3-bromopyruvate (3-BrPA) can inhibit glycolysis in tumor cells to reduce ATP production, resulting in apoptosis. However, as 3-BrPA is an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms. The results presented here reveal that 3-BrPA-induced apoptosis is caspase independent. Further, 3-BrPA induces the generation of reactive oxygen species in MDA-MB-231 cells, leading to mitochondria-mediated apoptosis. These results suggest that caspase-independent apoptosis may be induced by the generation of reactive oxygen species. In this study, we also demonstrated that 3-BrPA induces apoptosis through the downregulation of myeloid cell leukemia-1 (Mcl-1) in MDA-MB-231 breast cancer cells. The results of Mcl-1 knockdown indicate that Mcl-1 plays an important role in 3-BrPA-induced apoptosis. Further, the upregulation of Mcl-1 expression in 3-BrPA-treated MDA-MB-231 cells significantly increases cell viability. In addition, 3-BrPA treatment resulted in the downregulation of p-Akt, suggesting that 3-BrPA may downregulate Mcl-1 through the phosphoinositide-3-kinase/Akt pathway. These findings indicate that 3-BrPA induces apoptosis in breast cancer cells by downregulating Mcl-1 through the phosphoinositide-3-kinase/Akt signaling pathway.