Role of the phosphatidylinositol 3'-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/APO-2L is a member of the TNF superfamily and has been shown to have selective antitumor activity. We here show that TRAIL does not induce apoptosis in some non-small cell lung cancer (NSCLC) cells. These cells are resistant to TRAIL because of the phosphatidylinositol 3'-kinase (PI3-K)-dependent activation of Akt/protein kinase B. The expression of phospho-Akt varies at the functional level but not at the mRNA level in NSCLC cells. Akt induces cell survival in NSCLC cells by blocking the Bid cleavage, upstream of cytochrome c release in the mitochondrial-dependent apoptotic pathway. The use of PI3-K inhibitors, Wortmannin or LY-294002, down-regulates the active Akt and reverses cellular resistance to TRAIL. In addition, genetically altering Akt expression by transfecting dominant negative Akt, sensitizes NSCLC cells to TRAIL. Conversely, transfection of constitutively active Akt into cells that express low, constitutively active Akt, increases TRAIL resistance. Alternate to this approach, transfection with PTEN, a lipid phosphatase, promotes sensitivity to TRAIL, whereas a PTEN mutant (PTEN-G129E) at the catalytic site is inactive in dephosphorylating active Akt. Furthermore, the loss of PTEN activity or overexpression of PI3-K-dependent Akt/protein kinase B activity promotes the survival of NSCLC cells. Modulation of Akt activity by combining pharmacological drugs or genetic alterations of the Akt expression induces cellular responsiveness to TRAIL. Thus, TRAIL can be used to treat NSCLC-resistant cells when combined with agents that down-regulate Akt activity.
Department of Pharmaceutical Sciences, University of Maryland- School of Pharmacy, Greenebaum Cancer Center, Baltimore, Maryland 21201-1180, USA.
Karthikeyan
K
Kandasamy
Rakesh K
RK
Srivastava
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases; D008562:Membrane Glycoproteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C505653:TNFSF10 protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human; C506433:CASP9 protein, human