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.

FOXO1 Inhibits Tumor Cell Migration via Regulating Cell Surface Morphology in Non-Small Cell Lung Cancer Cells

“…The activity of FOXO transcription factors is mainly regulated by covalent modifications. Forkhead box protein O1 (FOXO1) is a major target protein for activated P13K/AKT signaling [23,24]. FOXO1 orchestrates programs of gene expression that regulate cell proliferation, apoptosis, and transition.…”

Estimates of linkage disequilibrium and effective population sizes in Chinese Merino (Xinjiang type) sheep by genome-wide SNPs

“…It is a member of the tumor necrosis factor receptor superfamily (Hu et al 1999) and plays a crucial role in hair follicle development, skin development, epithelial cell development, and epithelium development (Kojima et al 2000; Pispa et al 2008). FOXO1 functions on epithelium development and the epidermal growth factor receptor signaling pathway, as well as Wnt signaling pathway (Guan et al 2015; Mori et al 2014; Xu et al 2015). This gene, on OAR10 from 22,235,779 to 22,242,617 bp in sheep, belongs to the forkhead transcription factors.…”

FYN promotes breast cancer progression through epithelial-mesenchymal transition

“…As a tumor-suppressor, FOXO1 expression is low in endometrioid endometrial cancer cells (11) and non-small cell lung cancer (12) and inhibits prostate cancer cell migration and invasion (13). Recently, FOXO1 was proven to play key roles in drug resistance in tongue (14), non-small cell lung (15), ovarian (16) and prostate cancer (17).…”