Epithelial-mesenchymal transition (EMT) is an important process for cancer metastasis, drug resistance, and cancer stem cells. Activation of fibroblast growth factor receptor 1 (FGFR1) was found to promote EMT and metastasis in prostate and breast cancers, but the effects and mechanisms in lung cancer was unclear. In this study, we aimed to explore whether and how activation of FGFR1 promotes EMT and metastasis in FGFR1-amplified lung cancer. We show that activation of FGFR1 by its ligand fibroblast growth factor 2 (FGF2) promoted proliferation, EMT, migration, and invasion in FGFR1-amplified lung cancer cell lines H1581 and DMS114, whereas inhibition of FGFR1 suppressed these processes. FGFR1 activation upregulated expression of Sry-related HMG box 2 (SOX2) by downstream phosphorylated ERK1/2; moreover, the upregulation of SOX2 by autophosphorylation variant ERK2_R67S plasmid transfection was not suppressed by FGFR1 inhibitor AZD4547 or MEK/ERK inhibitor AZD6244 in vitro. And SOX2 expression was also significantly upregulated in ERK2_R67S lentivirus-transfected stable cell lines in vivo. Overexpression of SOX2 promoted cell proliferation, EMT, migration, and invasion. Importantly, activation of FGFR1 could not promote these processes in SOX2-silenced stable cell lines. In orthotopic and subcutaneous lung cancer xenograft models, inhibition of FGFR1 suppressed tumor growth, SOX2 expression, EMT, and metastasis in vivo; however, these processes caused by SOX2-overexpressing stable cell lines were not suppressed by FGFR1 inhibition. Higher expression of FGFR1 and SOX2 were positively correlated, and both were associated with shorter survival in lung cancer patients. In conclusion, our findings reveal that activation of FGFR1 promotes cell proliferation, EMT, and metastasis by the newly defined FGFR1-ERK1/2-SOX2 axis in FGFR1-amplified lung cancer.
Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research.
Purpose: Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.Experimental Design: We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups.Results: Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3mutant group and 36.8 months in the control group (P ¼ 0.006).Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed.
BACKGROUND AND PURPOSEThe histone acetyltransferase MOF is a member of the MYST family. In mammals, MOF plays critical roles by acetylating histone H4 at K16 and non-histone substrates such as p53. Here we have investigated the role of MOF in human lung cancer and possible new substrates of hMOF. EXPERIMENTAL APPROACHSamples of human non-small cell lung cancer (NSCLC) were used to correlate MOF with clinicopathological parameters and NF-E2-related factor 2 (Nrf2) downstream genes. 293T-cells were used to study interactions between MOF and Nrf2, and acetylation of Nrf2 by MOF. Mouse embryonic fibroblast and A549 cells were utilized to assess involvement of MOF in antioxidative and anti-drug responses. A549 cells were used to analysis the role of MOF in anti-drug response in vitro and in vivo. KEY RESULTShMOF was overexpressed in human NSCLC tissues and was associated with large tumour size, advanced disease stage and metastasis, and with poor prognosis. hMOF levels were positively correlated with Nrf2-downstream genes. MOF/hMOF physically interacted with and acetylated Nrf2 at Lys 588 . MOF-mediated acetylation increased nuclear retention of Nrf2 and transcription of its downstream genes. Importantly, MOF/hMOF was essential for anti-oxidative and anti-drug responses in vitro and regulated tumour growth and drug resistance in vivo in an Nrf2-dependent manner. CONCLUSION AND IMPLICATIONShMOF was overexpressed in human NSCLC and was a predictor of poor survival. hMOF-mediated Nrf2 acetylation and nuclear retention are essential for anti-oxidative and anti-drug responses. hMOF may provide a therapeutic target for the treatment of NSCLC. AbbreviationsARE, antioxidant response element; CDDP, cis-diamminedichloroplatinum; GCLM, glutamate-cysteine ligase modifier subunit; HO-1, haem oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; MEF, mouse embryonic fibroblast; MOF, males absent on the first; MSL, male-specific lethal; Nrf2, NF-E2-related factor 2; NQO1, NAD(P)H quinone oxidoreductase 1; NSCLC, non-small cell lung cancer; 5-FU, 5-fluorouracil
Purpose Epidermal growth factor receptor (EGFR) mutation-positive (EGFRmut+) non-small cell lung cancer (NSCLC) may be a unique orphan disease. Previous studies suggested that the telomerase reverse transcriptase (TERT) gene polymorphism is associated with demographic and clinical features strongly associated with EGFR mutations, e.g. adenocarcinoma histology, never-smoking history and female gender. We aim to test the association between TERT polymorphism and EGFRmut+ NSCLC. Experimental Design We conducted a genetic association study in Chinese NSCLC patients (n=714) and healthy controls (n=2,520), between the rs2736100 polymorphism and EGFRmut+ NSCLC. We further tested the association between the EGFR mutation status and mean leukocyte telomere length (LTL). The potential function of rs2736100 in lung epithelial cells was also explored. Results The rs2736100-C allele was significantly associated with EGFRmut+ NSCLC (OR=1.52, 95%CI=1.28–1.80, p=1.6×10−6) but not EGFRmut− NSCLC (OR=1.07, 95%CI=0.92–1.24, p=0.4). While NSCLC patients as a whole have significantly longer LTL compared to healthy controls (p≤10−13), the EGFRmut+ patients have even longer LTL compared to EGFRmut-patients (p=0.008). Meanwhile, rs2736100 was significantly associated with TERT mRNA expression in both normal and tumor lung tissues. All results remained significant after controlling for age, gender, smoking status and histology (p<0.05 for all tests). Moreover, the rs2736100 DNA sequence has an allele-specific affinity to nuclear proteins extracted from lung epithelial cells, which led to an altered enhancer activity of the sequence in vitro. Conclusion Our study suggests that telomerase and telomere function may be essential for carcinogenesis of EGFRmut+ NSCLC. Further investigation for the underlying mechanism is warranted.
The highest incidence of VTE is within 1 month after lung cancer surgery. High risk factors for VTE include incomplete surgical resection, postoperative use of anti-angiogenesis drugs, EGFR-TKI application and an increase in preoperative D-dimer level.
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