Regulation of Akt by EGF-R inhibitors, a possible mechanism of EGF-R inhibitor-enhanced TRAIL-induced apoptosis

• Published in: Biochemical and biophysical research communications Vol. 295; no. 2; pp. 515 - 518
• Main Authors: Park, Sang-Youel, Seol, Dai-Wu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2002
• Subjects: Akt; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins; Cell Line; EGF-R; ErbB Receptors - antagonists & inhibitors; Genistein; Genistein - pharmacology; Membrane Glycoproteins - physiology; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-akt; Pyrimidines - pharmacology; Quinazolines - pharmacology; Recombinant Proteins - metabolism; TNF-Related Apoptosis-Inducing Ligand; TRAIL; Tumor Necrosis Factor-alpha - physiology; TRAIL; Akt; EGF-R; Genistein; Apoptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(02)00719-2

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane cytokine and a potent inducer of apoptosis. Epidermal growth factor (EGF) signaling is well known to involve in tumor survival and overexpression of EGF receptor (EGF-R) attributes to decreased responsiveness to many available therapies in cancer treatment. We investigated whether EGF-R inhibitors enhance TRAIL-induced apoptosis. We exposed A549 cells to Genistein, PD153035, and PD158780 for 12 h and then treated with recombinant TRAIL protein. TRAIL alone induced 25% cell death after a 3-h treatment, but in cells pretreated with EGF-R inhibitors, TRAIL induced cell death to more than 70% after 3 h treatment. Genistein enhanced TRAIL-induced apoptosis in a time- and dose-dependent manner. Western blot analyses showed that pretreatment with Genistein down-regulated the protein levels of total Akt and phosphorylated active Akt. Genistein also decreased the protein level of Bcl-XL that is regulated by Akt. These molecules are well characterized to act against induction of apoptotic cell death. Therefore, our data suggest that EGF-R inhibitor may sensitize A549 cells to TRAIL-induced apoptosis by regulating expression of these proteins. EGF-R inhibitors may play an important role in the anti-cancer activity of TRAIL protein, especially in TRAIL-resistant tumors that arise by expressing constitutively active Akt.