Lung cancer (Amsterdam, Netherlands) · 2013
Activation of Akt involves resistance to NF-κB inhibition and abrogation of both triggers synergistic apoptosis in lung adenocarcinoma cells.
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Togano Tomiteru, Watanabe Mariko, Itoh Kinji, Umezawa Kazuo, Masuda Noriyuki, Higashihara Masaaki, Horie Ryouichi
Аннотация
OBJECTIVES: Although nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)-Akt-mTOR comprise key pathways, their interrelationship in lung cancer cell survival is poorly understood and needs further analyses.
MATERIALS AND METHODS: We examined the activation of the NF-κB and Akt-mTORC1-p70 S6 kinase (S6K) pathways and the effect of inhibitors for NF-κB, mTORC1, and Akt using fresh lung adenocarcinoma cells.
RESULTS: The cases used for this study showed constitutive NF-κB activity; however, all cases but one showed resistance to NF-κB inhibition. Further examination revealed that the resistant cases were also active in the Akt-mTORC1-S6K pathway. These cases were insensitive to mTORC1 inhibition but sensitive to Akt inhibition. Akt inhibition recovered sensitivity to NF-κB inhibition and dual inhibition showed a synergistic effect on apoptosis induction.
CONCLUSION: These results indicate that the activation of Akt involves resistance to NF-κB inhibition and both pathways synergistically support the survival of lung adenocarcinoma cells. The results also indicate that inhibition of the mTORC1-S6K pathway does not inhibit the survival of these cells.
MATERIALS AND METHODS: We examined the activation of the NF-κB and Akt-mTORC1-p70 S6 kinase (S6K) pathways and the effect of inhibitors for NF-κB, mTORC1, and Akt using fresh lung adenocarcinoma cells.
RESULTS: The cases used for this study showed constitutive NF-κB activity; however, all cases but one showed resistance to NF-κB inhibition. Further examination revealed that the resistant cases were also active in the Akt-mTORC1-S6K pathway. These cases were insensitive to mTORC1 inhibition but sensitive to Akt inhibition. Akt inhibition recovered sensitivity to NF-κB inhibition and dual inhibition showed a synergistic effect on apoptosis induction.
CONCLUSION: These results indicate that the activation of Akt involves resistance to NF-κB inhibition and both pathways synergistically support the survival of lung adenocarcinoma cells. The results also indicate that inhibition of the mTORC1-S6K pathway does not inhibit the survival of these cells.
Предметные рубрики MeSH
AdenocarcinomaAgedApoptosisBenzamidesCell SurvivalCells, CulturedCyclohexanonesDrug SynergismFemaleHeterocyclic Compounds, 4 or More RingsHumansLung NeoplasmsMaleMechanistic Target of Rapamycin Complex 1Middle AgedMultiprotein ComplexesNF-kappa BNeoplasm StagingOncogene Protein v-aktRibosomal Protein S6 Kinases, 70-kDaSignal TransductionSirolimusTOR Serine-Threonine KinasesTetrazoles