title: Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells.
abstract: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective clinical therapies for advanced non-small cell lung cancer (NSCLC) patients, while resistance to TKIs remains a serious problem in clinical practice. Recently, it has been proposed that targeting mTOR could overcome TKI resistance in NSCLC cells. Forkhead box class O1 (FOXO1) has emerged as an important rheostat that modulates the activity of Akt and mTOR signaling pathway. However, the role of FOXO1 and related regulatory mechanism in TKI resistance in NSCLC remain largely unknown. Here, we find that mTOR-AKT-FOXO1 signaling cascade is deregulated in TKI-resistant NSCLC cells and that FOXO1 was highly phosphorylated and lowly acetylated upon erlotinib treatment. Combination of mTOR or PI3K inhibitor and erlotinib overcomes TKI resistance to inhibit cell growth and induce apoptosis in TKI-resistant NSCLC cells. Furthermore, the phosphorylation and acetylation of FOXO1 are reversely modulated by mTORC2-AKT signaling pathway. FOXO1 mutation analyses reveal that FOXO1 acetylation inhibits cell proliferation and promotes NSCLC cell apoptosis, while the phosphorylation of FOXO1 plays opposite roles in NSCLC cells. Importantly, increasing FOXO1 acetylation by a HDAC inhibitor, depsipeptide, overcomes TKI resistance to effectively induce TKI-resistant NSCLC cell apoptosis. Together, FOXO1 plays dual roles in TKI resistance through posttranslational modifications in NSCLC and this study provides a possible strategy for treatment of TKI-resistant NSCLC patients.
authors.affiliation: Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University, 197 Rui Jin Road II, Shanghai, 200025, People's Republic of China.
authors.forename: Zhi-hong
authors.initials: ZH
authors.lastname: Xu
authors.forename: Wen-wen
authors.initials: WW
authors.lastname: Shun
authors.forename: Jun-biao
authors.initials: JB
authors.lastname: Hang
authors.forename: Bei-li
authors.initials: BL
authors.lastname: Gao
authors.forename: Jia-an
authors.initials: JA
authors.lastname: Hu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011499:Protein Processing, Post-Translational; D011799:Quinazolines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D058570:TOR Serine-Threonine Kinases; C085126:FOXO1 protein, human; C546842:MTOR protein, human