Activation of the Akt survival pathway contributes to TRAIL resistance in cancer cells.
The mechanism of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer cells is not fully understood. Here, we show that the Akt survival pathway plays an important role in TRAIL resistance in human cancer cells. Specifically, we found that TRAIL treatment activates the Akt survival pathway and that inhibition of this pathway by the PI3K inhibitor LY294002 or knockdown of Akt sensitizes resistant cancer cells to TRAIL. Since Akt is negatively regulated by the tumor suppressor PTEN, we examined the TRAIL sensitivity in PTEN knockdown mouse prostate epithelial cells and found that PTEN(-/-) cells are more resistant than PTEN(+/+) cells while the sensitivity of PTEN(+/-) cells fell in between. Further, we showed that overexpression of a mutant PTEN confers TRAIL resistance in PTEN(+/+) cells, supporting a role of PTEN in TRAIL sensitivity. In TRAIL resistant breast T47D cells, overexpression of the mutant PTEN further increased their resistance to TRAIL. Taken together, our data indicate that inactivation of functional PTEN and the consequent activation of the Akt pathway prevents TRAIL-induced apoptosis, leading to TRAIL resistance. Therefore, our results suggest that TRAIL resistance can be overcome by targeting PTEN or the Akt survival pathway in cancer cells.
Xu
Jing
J
Program in Molecular Biology & Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
Zhou
Jun-Ying
JY
Wei
Wei-Zen
WZ
Wu
Gen Sheng
GS
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D053221:TNF-Related Apoptosis-Inducing Ligand; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse