Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-09, Vol.61 (17), p.6569-6576
• Main Authors: Yu, W, Liao, Q Y, Hantash, F M, Sanders, B G, Kline, K
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 2; Apoptosis - drug effects; Apoptosis - physiology; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; DNA-Binding Proteins; Enzyme Activation; ets-Domain Protein Elk-1; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacology; p38 Mitogen-Activated Protein Kinases; Phosphorylation - drug effects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Tocopherols; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - drug effects; Tumor Cells, Cultured; Vitamin E - analogs & derivatives; Vitamin E - pharmacology
• ISSN: 0008-5472

RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.