title: Activation of Akt involves resistance to NF-κB inhibition and abrogation of both triggers synergistic apoptosis in lung adenocarcinoma cells.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Minami-ku, Kitasato, Sagamihara, Kanagawa 252-0374, Japan.
authors: Tomiteru
authors: T
authors: Togano
authors: Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Minami-ku, Kitasato, Sagamihara, Kanagawa 252-0374, Japan.
authors: Mariko
authors: M
authors: Watanabe
authors: Department of Pathology, School of Medicine, Toho University, 5-21-16 Ohmorinishi, Ohta-ku, Tokyo 143-8540, Japan.
authors: Kinji
authors: K
authors: Itoh
authors: School of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan.
authors: Kazuo
authors: K
authors: Umezawa
authors: Department of Respiratory Medicine, School of Medicine, Kitasato University, 1-15-1 Minami-ku, Kitasato, Sagamihara, Kanagawa 252-0374, Japan.
authors: Noriyuki
authors: N
authors: Masuda
authors: Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Minami-ku, Kitasato, Sagamihara, Kanagawa 252-0374, Japan.
authors: Masaaki
authors: M
authors: Higashihara
authors: Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Minami-ku, Kitasato, Sagamihara, Kanagawa 252-0374, Japan. Electronic address: rhorie@med.kitasato-u.ac.jp.
authors: Ryouichi
authors: R
authors: Horie
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009367:Neoplasm Staging; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D006576:Heterocyclic Compounds, 4 or More Rings; C501199:KP372-1; D046912:Multiprotein Complexes; D016328:NF-kappa B; D013777:Tetrazoles; C464444:dehydroxymethylepoxyquinomicin; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Akt; DHMEQ; Lung adenocarcinoma; NF-κB; Rapamycin; S6K