Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • It is increasingly evident that many metabolic genes are ass

    2023-01-05

    It is increasingly evident that many metabolic genes are associated with cancer progression of various tumor cells, including NSCLC. In particular, GLUT1 overexpression has been reported in NSCLC, and correlations between GLUT1 expression and a number of clinical parameters such as gender, smoking status, tumor size, pathological subtypes, differentiation and poor prognosis have been demonstrated in NSCLC patients [13], [14], [15], [16], [17]. It has also been reported that the overexpression of ACLY correlates with advanced stage, the presence of pleural invasion, poor differentiation, and poor outcome in patients with lung adenocarcinoma [18]. Our results support these previous findings that GLUT1 and ACLY expression have potential utility as prognostic markers. There is a connection between glucose metabolism and fatty salubrinal mg biosynthesis in tumor cells because glucose metabolism provides 60% of the carbon used for fatty acid biosynthesis [20]. In particular, GLUT1 expression is closely related to that of ACLY, because ACLY functions as a crosslink between glycolysis and lipogenesis [21]. High levels of glucose increases ACLY acetylation, which inhibits its ubiquitination and degradation, leading to accumulation of ACLY in cells. In contrast, when glucose is limited, ACLY is not acetylated and can therefore be ubiquitinated, leading to ACLY degradation [22]. However, ACLY degradation results in the accumulation of citrate in the cytoplasm, leading to inhibition of glycolysis [23]. Moreover, glucose analogs that inhibit glycolytic enzymes, as well as ACLY inhibitors, suppress tumor cell proliferation in vitro and in vivo[24], [25], [26]. Thus, these studies provide evidence that overexpression of both GLUT1 and ACLY in cancer cells can contribute to rapid proliferation. The existing evidence also indicates that co-expression of glucose and lipid metabolism confers a powerful growth advantage in terms of cell-environment interactions. Upregulation of glycolysis produces lactic acid, which dysregulates the pH of cancer cells. Acidosis promotes the destruction of cell cycle checkpoints and apoptotic mechanisms [27]. Consequently, after substantial cell mortality, acidosis selects for resistant phenotypes that are able to maintain higher invasion and higher motility for multiple generations [28]. It has been reported that lipogenesis is a major resistance mechanism in an acidic microenvironment, because upregulation of fatty acid synthase (FASN), which is a key metabolic enzyme that catalyzes the terminal steps in lipogenesis, protects cells from death by inhibiting the intrinsic pathway of apoptosis [29]. Based on the above-mentioned reports, it may be assumed that cell populations that exhibit upregulation of both glucose and lipid metabolic genes would show a high degree of biological malignancy by responding to the large demand for cellular building blocks and the need to adapt to an acidic microenvironment. This model supports our data that demonstrated that the double-positive GLUT1 and ACLY status showed the worst outcome, whereas the double-negative status exhibited the best outcome in NSCLC patients. Additionally, our data are broadly consistent with findings from a previous clinical study, which demonstrated that the levels of a combination of four metabolic genes including PGI, ACLY, RRM2 and TYMS, have a strong predictive value for breast cancer patient outcome [3]. In the present study, although the double-positive status did not show an independent prognostic impact in the multivariate analysis of all of the patients, we further analyzed the correlation of lymph node status with GLUT1 and ACLY expression and clinical features. Our data may show that a double-positive status was an independent prognostic factor for outcome in node-negative patients with NSCLC, but not in node-positive patients. This prognostic ability was consistent with the observations of previous studies in which high expression of hypoxia-inducible factor-1 (HIF-1), which is broadly known as crucial regulator of GLUT1 expression and lipogenesis through a transcriptional mechanism, was associated with poor prognosis in node-negative patients with NSCLC, but not in node-positive cases [30], [31], [32]. Thus, the most likely explanation of our findings is that the expression of GLUT1 and ACLY, as well as that of HIF-1, is strongly dependent on the hypoxic tumor environment. We further postulated that the reason why the double-positive status did not have a prognostic impact in node-positive patients may result from constitutive activation of metabolic genes and re-oxygenation of the tumor environment by vascular endothelial growth factor (VEGF).