bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019‒04‒14
two papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Glucose transporter 3 gene variant is associated with survival outcome of patients with non-small cell lung cancer after surgical resection.
  2. Apigenin Combined With Gefitinib Blocks Autophagy Flux and Induces Apoptotic Cell Death Through Inhibition of HIF-1α, c-Myc, p-EGFR, and Glucose Metabolism in EGFR L858R+T790M-Mutated H1975 Cells.
  1. Gene. 2019 Apr 04. pii: S0378-1119(19)30353-1. [Epub ahead of print]
    Glucose transporter 3 gene variant is associated with survival outcome of patients with non-small cell lung cancer after surgical resection.
    Do SK, Choi SH, Lee SY, Choi JE, Hong MJ, Kang HG, Lee WK, Lee EB, Shin KM, Jeong JY, Lee YH, Seo H, Yoo SS, Lee J, Cha SI, Kim CH, Seok Y, Cho S, Jheon S, Park JY.
      This study was conducted to explore whether polymorphisms of glucose transporter 3 (GLUT3) gene affect the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Four single nucleotide polymorphisms (SNPs) in GLUT3 were investigated in a total of 782 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. Among the four SNPs investigated, GLUT3 rs7309332C>T was significantly associated with OS and DFS in multivariate analyses. The SNP was associated with significantly worse OS (adjusted hazard ratio [aHR] = 1.62, 95% confidence interval [CI] = 1.04-2.53, P = 0.03, under recessive model), and worse DFS (aHR = 1.64, 95% CI = 1.18-2.29, P = 0.003, under recessive model). When stratified by tumor histology, the association between the GLUT3 rs7309332C>T and OS/DFS was not limited to either squamous cell carcinoma (SCC) or adenocarcinoma (AC), although the significant association remained only in AC for OS (P = 0.40 for SCC and P = 0.04 for OS) and only in SCC for DFS (P = 0.03 for SCC and P = 0.08 for OS). When AC patients were stratified according to EGFR mutation status, the SNP was significantly associated with DFS in patients with EGFR mutant tumors (aHR = 2.47, 95% CI = 1.15-5.30, P = 0.02, under recessive model), but not in those with EGFR wild-type tumors. This study suggests that genetic variation in GLUT3 may be useful in predicting survival of patients with early stage NSCLC.
    Keywords:  GLUT3; Non-small cell lung cancer; Polymorphism; Surgery; Survival
    DOI:  https://doi.org/10.1016/j.gene.2019.04.013
  2. Front Pharmacol. 2019 ;10 260
    Apigenin Combined With Gefitinib Blocks Autophagy Flux and Induces Apoptotic Cell Death Through Inhibition of HIF-1α, c-Myc, p-EGFR, and Glucose Metabolism in EGFR L858R+T790M-Mutated H1975 Cells.
    Chen Z, Tian D, Liao X, Zhang Y, Xiao J, Chen W, Liu Q, Chen Y, Li D, Zhu L, Cai S.
      Cancer cells are characterized by abnormally increased glucose uptake and active bio-energy and biosynthesis to support the proliferation, metastasis, and drug resistant survival. We examined the therapeutic value of the combination of apigenin (a natural small-molecule inhibitor of Glut1 belonging to the flavonoid family) and gefitinib on epidermal growth factor receptor (EGFR)-resistant mutant non-small cell lung cancer, to notably damage glucose utilization and thus suppress cell growth and malignant behavior. Here, we demonstrate that apigenin combined with gefitinib inhibits multiple oncogenic drivers such as c-Myc, HIF-1α, and EGFR, reduces Gluts and MCT1 protein expression, and inactivates the 5' adenosine monophosphate-activated protein kinase (AMPK) signaling, which regulates glucose uptake and maintains energy metabolism, leading to impaired energy utilization in EGFR L858R-T790M-mutated H1975 lung cancer cells. H1975 cells exhibit dysregulated metabolism and apoptotic cell death following treatment with apigenin + gefitinib. Therefore, the combined apigenin + gefitinib treatment presents an attractive strategy as alternative treatment for the acquired resistance to EGFR-TKIs in NSCLC.
    Keywords:  AMPK; apigenin; apoptosis; autophagy; combination; gefitinib; mutation; non-small cell lung cancer
    DOI:  https://doi.org/10.3389/fphar.2019.00260
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