FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop

Abstract

Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development.

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma

“…The latter has been repeatedly implicated in drug-resistant solid cancers; e.g., in retinoblastoma [ 35 ], bladder cancer [ 36 ] and colorectal cancer [ 37 ], in which the heightened drug-efflux activity could be functionally linked to FOXM1-dependent upregulation of ABCC4, ABCG2 and ABCC10, respectively. Also playing a role may be other pathways of drug resistance that operate in solid tumors [ 38 ]; e.g., inhibition of ubiquitination-dependent FOXM1 degradation via interacting proteins, such as OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) [ 39 ]; crosstalk of FOXM1 with other cellular signal transduction pathways, such as HGF / Met (hepatocyte growth factor / Met proto-oncogene, receptor tyrosine kinase) [ 40 ] and AKT (AKT serine / threonine kinase 1) [ 41 ]; and metabolic changes that effect increased oxidative defense capacity, as seen in radio-resistant head and neck squamous cell carcinoma [ 42 ]. Targeting the interactions and pathways described above – perhaps in conjunction with targeting FOXM1 directly using established [ 43 ] or emerging [ 44 ] small-drug inhibitors – may afford the re-sensitization of relapsed FOXM1 High myeloma to Bz and other drugs that were effective at earlier stages of myeloma therapy.…”

Akt/FoxM1 signaling pathway-mediated upregulation of MYBL2 promotes progression of human glioma

“…FoxM1 is a member of the Forkhead box (Fox) transcription factor family, which has been shown to be over-expressed in various cancers and studies have shown that alterations in FoxM1 signaling were associated with carcinogenesis. FoxM1 is substantially elevated in several aggressive human carcinomas and can contribute to oncogenesis in many tissue types, including breast [ 12 ], hepatocellular [ 13 ], prostate [ 14 ], lung [ 15 ], and colorectal cancers [ 16 ]. Aberrant FoxM1expression was found to be a common molecular alteration in malignant glioma [ 17 ].…”

TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

“…(5,28) Our previous microarray data and various other studies indicated that both EGFR and MET can regulate FOXM1 expression. (6,(23)(24)(25)(26)(27) Here we report that TCPOBOP-driven FOXM1 induction and its downstream gene network activation was remarkably impaired in [MET KO + EGFRi] mice, which might contribute to attenuated proliferation in our model. Conversely, the inverse phenotype to our model (i.e., increased proliferation but reduced expression of drug metabolic enzymes) previously reported in β-catenin KO mice following TCPOBOP treatment was attributed to increased FOXM1 levels.…”

“…Our previous data and several other reports indicated that both MET and EGFR can regulate an important transcription factor, FOXM1, which governs transcription of genes important for DNA replication and mitosis. (6,(23)(24)(25)(26)(27) FOXM1 is considered to be critical for inducing TCPOBOP-mediated hepatocyte proliferation. (3,5,14,16,22,28) Consistent with these previous reports, FOXM1 was remarkably induced by TCPOBOP at all of the time points in control mice with peak induction (10-fold) coinciding with the time point of peak proliferation (day 2) ( Fig.…”