bims-meluca Biomed news
on Metabolism of non-small cell lung carcinoma
Issue of 2018‒12‒30
two papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Exp Cell Res. 2018 Dec 20. pii: S0014-4827(18)30988-1. [Epub ahead of print]
    McDonald AJ, Curt KM, Patel RP, Kozlowski H, Sackett DL, Robey RW, Gottesman MM, Bates SE.
      Hexokinase 1 and 2 have been shown to inhibit Bak- and Bax-mediated apoptosis, leading us to combine the histone deacetylase inhibitor romidepsin with clotrimazole or bifonazole, two compounds that reportedly decrease mitochondrial localization of hexokinases. Cancer cell lines derived from breast, kidney, lung, colon or ovarian cancers were treated with a short-term exposure to 25ng/ml romidepsin combined with either clotrimazole or bifonazole. The combination of romidepsin with 25µM of clotrimazole or bifonazole resulted in increased annexin staining compared to cells treated with any of the drugs alone. Cell death was caspase-mediated, as the pan-caspase inhibitor Q-VD-OPh was found to inhibit apoptosis induced by the combination. A549 lung cancer cells or HCT-116 cells deficient in Bak and Bax were also resistant to apoptosis with the combination implicating the intrinsic apoptotic pathway. We found that a 24h treatment with clotrimazole or bifonazole decreased total hexokinase 2 expression, resulting in a 76% or 60% decrease, respectively, of mitochondrial expression of hexokinase 2. Mitochondrial hexokinase 1 levels increased 2-fold or less. Our work suggests that the combination of a short-term romidepsin treatment with bifonazole or clotrimazole leads to increased apoptosis, most likely due to decreased mitochondrial expression of hexokinase 2.
    Keywords:  apoptosis; hexokinase; histone deacetylase inhibitor; romidepsin
    DOI:  https://doi.org/10.1016/j.yexcr.2018.12.012
  2. Thorac Cancer. 2018 Dec 26.
    Lee YH, Do SK, Lee SY, Kang HG, Choi JE, Hong MJ, Lee JH, Lee EB, Jeong JY, Shin KM, Lee WK, Seok Y, Cho S, Yoo SS, Lee J, Cha SI, Kim CH, Jheon S, Park JY.
      This study was conducted to investigate the associations between polymorphisms of genes involved in the LKB1 pathway and the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Twenty-three single nucleotide polymorphisms (SNPs) in the LKB1 pathway were investigated in 782 patients with NSCLC who underwent curative surgery. The association of SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. Among the 23 SNPs investigated, TSC2 rs30259G > A was associated with significantly worse OS and DFS (adjusted hazard ratio for OS 1.88, 95% confidence interval 1.21-2.91, P = 0.005; adjusted hazard ratio for DFS 1.65, 95% confidence interval 1.15-2.38, P = 0.01, under codominant models, respectively). Subgroup analysis showed that SNPs were significantly associated with survival outcomes in squamous cell carcinoma, ever-smokers, and stage I, but not in adenocarcinoma, never-smokers, and stage II-IIIA. The results suggest that TSC2 rs30259G > A may be useful to predict prognosis in patients with NSCLC, especially squamous cell carcinoma, after curative surgery.
    Keywords:   TSC2; Lung cancer; polymorphism; prognosis
    DOI:  https://doi.org/10.1111/1759-7714.12951