bims-meluca 2020-03-22 papers

Cancer Lett. 2020 Mar 11. pii: S0304-3835(20)30126-9. [Epub ahead of print]

AMPK-Dependent Phosphorylation of HDAC8 Triggers PGM1 Expression to Promote Lung Cancer Cell Survival under Glucose Starvation.

Li Y, Liang R, Sun M, Li Z, Sheng H, Wang J, Xu P, Liu S, Yang W, Lu B, Zhang S, Shan C.

Cancer cells undergo metabolic reprogramming to sustain their own survival under an environment of increased energy demand; however, the mechanism by which cancer cells ensure survival under glucose deprivation stressed conditions remains elusive. Here, we show that deprivation of glucose, dramatically activated the glycogen pathway, accompanied by elevated phosphoglucomutase 1 (PGM1) expression. We further identified that AMP-activated protein kinase (AMPK) stimulated PGM1 expression by inducing histone deacetylase 8 (HDAC8) phosphorylation. Moreover, we demonstrated that glucose deprivation-induced AMPK activation stimulated the translocation of HDAC8 from the nucleus to the cytoplasm, consequently disrupting the binding between HDAC8 and histone 3. PGM1 expression was also found to be critical for lung cancer glycolysis, the oxidative pentose phosphate pathway, and oxidative phosphorylation under glucose deprivation conditions, and further led to the aberrant expression of metabolic enzymes involved in glucose metabolism mediated by ERK1/2. Finally, PGM1 was found to be highly expressed in lung cancer tissues from patients, which correlated with a poor prognosis. Taken together, these results revealed that AMPK activation by glucose deprivation leads to enhanced PGM1 expression, an essential component of the metabolic switch, to facilitate cancer progression, suggesting PGM1 as promising anti-cancer treatment targets.

Keywords: AMP-activated protein kinase (AMPK); Glucose deprivation; Lung cancer; Metabolic reprogramming; Phosphoglucomutase 1 (PGM1)

DOI: https://doi.org/10.1016/j.canlet.2020.03.007

J Pharm Pharmacol. 2020 Mar 20.

Kruppel-like factor 2 disturb non-small cell lung cancer energy metabolism by inhibited glutamine consumption.

Xiao S, Jin-Xiang Y, Long T, Xiu-Rong L, Hong G, Jie-Cheng Y, Fei Z.

OBJECTIVES: Metabolic reprogramming is well accepted as a hallmark of cancer. This study aimed to explore the role of Kruppel-like factor 2 (KLF2) in aerobic glycolysis and glutamine consumption of energy metabolism in non-small cell lung cancer (NSCLC) cells.METHODS: Two different NSCLC cells, A549 and NCI-H1299, were used to investigate the role of KLF2 in glycolysis and glutamine consumption by tracer technique and KLF2 transfection.
KEY FINDINGS: The results showed that overexpression KLF could inhibit the energy metabolism and proliferation of NSCLC cells, but had no significant effect on glycolysis reaction and only affected the glutamine consumption of NSCLC cells. In NSCLC cells exposed to glutamine deprivation, the effect of overexpression of KLF2 on cell proliferation and energy metabolism disappeared. It was found that KLF2 could inhibit the expression of glutaminase (GLS) by metabolite tracing technique and so on. However, when GLS inhibitors were given to overexpressing KLF2 NSCLC cells, the intervention effect of KLF2 disappeared.
CONCLUSIONS: Kruppel-like factor 2 could decrease the level of glutamine, participate in the consumption of glutamine by cancer cells, and then inhibit the energy metabolism of cancer cells.

Keywords: KLF2; NSCLC; aerobic glycolysis; glutaminase; glutamine consumption

DOI: https://doi.org/10.1111/jphp.13252

Cell Death Dis. 2020 Mar 18. 11(3): 195

Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness.

Chang YC, Yang YF, Chiou J, Tsai HF, Fang CY, Yang CJ, Chen CL, Hsiao M.

Drug resistance remains a serious issue of clinical importance and is a consequence of cancer stemness. In this study, we showed that the level of Aldolase A (ALDOA) expression is significantly associated with the IC50 value of chemotherapy drugs in lung cancer. Our data revealed that ALDOA overexpression resulted in a significant increase of lung tumor spheres. The use of ingenuity pathway analysis (IPA) resulted in the identification of POU5F1 (Oct4) as the leading transcription factor of ALDOA. We observed high expression of ALDOA, Oct4 and stemness markers in collected spheroid cells. DUSP4 and TRAF4 were confirmed as major downstream targets of the ALDOA-Oct4 axis. Knockdown of these molecules significantly decreased the stemness ability of cells. In addition, we investigated whether miR-145 targets the 3'-UTR of Oct4 and is regulated by ALDOA due to the involvement of ALDOA in glycolysis and metabolic reprogramming. Furthermore, we constructed several mutant forms of ALDOA that disrupted its enzymatic activity and showed that they still induced significant in vitro sphere formation and in vivo tumorigenicity. These results demonstrated that ALDOA-mediated spheroid formation is independent of its enzymatic activity. In the clinical component, we also showed that the combination of ALDOA and TRAF4 or DUSP4 is positively correlated with poor overall survival in a xenograft model and cancer patients through immunohistochemical analyses. The results of our study revealed novel functional roles of ALDOA in inducing cancer stemness via the inhibition of miR-145 expression and the activation of Oct4 transcription. These findings offer new therapeutic strategies for modulation of lung cancer stemness to enhance chemotherapeutic responses in lung cancer patients.

DOI: https://doi.org/10.1038/s41419-020-2387-2

World J Nucl Med. 2020 Jan-Mar;19(1):19(1): 8-14

Prognostic value of metabolic parameters measured by 18F-fluorodeoxyglucose positron emission tomography-computed tomography in surgically resected non-small cell lung cancer patients.

Mathew B, Purandare NC, Puranik A, Shah S, Agrawal A, Pramesh CS, Karimundackal G, Jiwnani S, Rangarajan V.

18F-fluorodeoxyglucose positron emission tomography-computed tomography-derived metabolic parameters can play a role in prognostication. We investigated the prognostic value of various metabolic parameters such as maximum standardized uptake value (SUVmax), mean SUV (SUVmean), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) in surgically resected non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed 153 patients with NSCLC who underwent surgical resection. The SUVmax, SUVmean, WBMTV, and WBTLG of the tumor were measured. Continuous PET parameters were stratified by receiver operating characteristic curve analysis. Prognostic factors were estimated using the Kaplan-Meier method and Cox proportional hazards model. The median follow-up was 36.9 months. Fifty-six patients died and 78 patients had recurrence. On univariate analysis, tumor-node-metastasis (TNM) stage; male sex; no adjuvant treatment; and higher SUVmax, SUVmean, WBMTV, and WBTLG were statistically significant and were associated with poor overall survival (OS). TNM stage; no adjuvant treatment; and higher SUVmax, SUV mean, WBMTV, and WBTLG were statistically significant and were associated with poor disease-free survival (DFS). On multivariate analysis, higher WBTLG (hazard ratio [HR] = 3.08, P = 0.007) for DFS and higher WBTLG (HR = 2.70, P = 0.041) and TNM staging (HR = 1.63, P = 0.035) for OS were statistically significant. Whole-body tumor burden assessment with TLG has independent prognostic value in patients with operated lung cancer. Incorporation of TLG into clinical practice can identify patients benefitted from additional therapy.

Keywords: 18F-fluorodeoxyglucose positron emission tomography-computed tomography; lung cancer; metabolic parameters; prognostic value; total lesion glycolysis

DOI: https://doi.org/10.4103/wjnm.WJNM_26_19