Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer.

Abstract

There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial‑derived activator of caspase/direct IAP‑binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA‑MB‑231 and MCF‑7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161‑dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor‑interacting protein kinase‑1 via small interfering RNA protected the cells from LCL161‑induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds.

• Authors: Gongsheng Jin, Yadong Lan, Fusheng Han, Yiming Sun, Zhe Liu, Mingliang Zhang, Xianfu Liu, Xiaojing Zhang, Jianguo Hu, Hao Liu, Benzhong Wang
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 13 Issue 1 Pg. 359-66 (Jan 2016) ISSN: 1791-3004 [Electronic] Greece
• PMID: 26573429 (Publication Type: Journal Article)

Chemical References

• AGFG1 protein, human
• Amino Acid Chloromethyl Ketones
• Caspase Inhibitors
• Inhibitor of Apoptosis Proteins
• LCL161
• Nuclear Pore Complex Proteins
• RNA-Binding Proteins
• Thiazoles
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (metabolism, pathology)
• Caspase Inhibitors (pharmacology)
• Caspases (metabolism)
• Cell Proliferation (drug effects)
• Female
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• MCF-7 Cells
• Membrane Potential, Mitochondrial (drug effects)
• Necrosis
• Nuclear Pore Complex Proteins (metabolism)
• Proteolysis (drug effects)
• RNA-Binding Proteins (metabolism)
• Thiazoles (pharmacology)