Microarray analyses of human MDA-MB-435 breast cancer cells treated with vitamin E analog 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy acetic acid (alpha-TEA) showed over 400 genes to be modulated. Thirty-four genes deemed of interest based on potential involvement in anticancer activities of alpha-TEA fell into six categories: apoptosis related, signal transduction, cell cycle related, cell adhesion and motility, transcriptional regulators, and membrane traffic related. The gene (PMAIP1) for NOXA was studied further. NOXA mRNA and protein levels were elevated in a time and dose-dependent fashion following alpha-TEA treatment. Functional knockdowns using small interfering RNA (siRNA) showed NOXA to contribute to alpha-TEA-induced apoptosis. A correlation between alpha-TEA's ability to upregulate NOXA and induce apoptosis was seen among several human breast cancer cell lines. Efforts to identify upstream regulators of NOXA in alpha-TEA-induced apoptosis identified the necessity of both c-Jun N-terminal kinase (JNK) activation and p73 expression. Additionally, protein levels of full length p73 were decreased by JNK siRNA treatment, suggesting that the signal transduction module of JNK-p73-NOXA is involved in alpha-TEA induced apoptosis of human breast cancer cells. Taken together, these findings suggest a role for JNK activation in mediating full length p73 expression and add to our understanding of the mechanisms of anticancer actions of alpha-TEA, a potential chemotherapeutic agent.
(c) 2007 Wiley-Liss, Inc.