Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand.
TRAIL/Apo2L is a pro-apoptotic cytokine that is capable of inducing apoptosis in a wide variety of cancer cells but not in normal cells. Among various molecular strategies by which cancer cells evade apoptosis, PI3K/Akt signaling represents a dominant survival pathway. In this report, we investigated the role of PI3K/Akt pathway in TRAIL-induced apoptotic death in human bladder cancer cells. We observed that RT4 cells had very low level of constitutively active Akt and were sensitive to TRAIL, whereas UM-UC-3 and T24 cells had higher levels of constitutively active Akt and were resistant to TRAIL. Downregulation of constitutively active Akt by PI3K inhibitors, wortmannin and LY294002, reversed cellular resistance to TRAIL. However, transfecting constitutively active Akt into RT4 cells increased Akt activity and inhibited TRAIL-induced apoptosis. These results suggest that elevated Akt activity protects UM-UC-3 and T24 cells from TRAIL-induced apoptosis, and the PI3K/Akt signaling might inhibit apoptotic signals. Thus, the modulation of Akt activity by combining pharmacological drugs or genetic alterations of the Akt expression could induce cellular responsiveness to TRAIL and PI3K/Akt signaling pathway could serve as a novel target for therapeutic intervention in bladder cancer.
Oka
Natsuo
N
Department of Urology, The University of Tokushima Graduate School Institute of Health Biosciences, Tokushima, Japan. natsuoka@clin.med.tokushima-u.ac.jp
Tanimoto
Shuji
S
Taue
Ryuichi
R
Nakatsuji
Hiroyoshi
H
Kishimoto
Tomoteru
T
Izaki
Hirofumi
H
Fukumori
Tomoharu
T
Takahashi
Masayuki
M
Nishitani
Masaaki
M
Kanayama
Hiro-omi
HO
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology*
D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C505653:TNFSF10 protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human