bims-meluca 2020-03-29 papers

Cell Oncol (Dordr). 2020 Mar 26.

PFKP is highly expressed in lung cancer and regulates glucose metabolism.

Jianfei Shen, Zixian Jin, Haiyan Lv, Ke Jin, Kangberee Jonas, Chengchu Zhu, Baofu Chen.

PURPOSE: Although it has been reported that up-regulation of phosphofructokinase (PFK) expression is a major feature of malignant tumors, the role of platelet type PFK (PFKP) in tumor initiation and progression is as yet poorly understood. The objective of this study was to evaluate PFKP expression in lung cancer and its effect on glycolysis, and to explore correlations between PFKP expression levels and clinical lung cancer patient features.
METHODS: PFKP mRNA expression levels in cancer tissues and adjacent normal tissues were compared using The Cancer Genome Atlas (TCGA) database. PFKP mRNA and protein expression levels in fresh lung cancer tissues and cell lines were assessed using quantitative real-time PCR and Western blotting. Immunohistochemistry (IHC) was used to assess PFKP expression in 150 archival lung adenocarcinoma samples, after which follow-up data and their correlations with clinical features and patient prognosis were evaluated. A retroviral shRNA-mediated method was used to construct stable cell lines expressing low levels of PFKP. Glucose, lactate and adenosine triphosphate concentrations in the cell culture supernatants were determined using enzymatic, spectrophotometric and enzyme-linked immunosorbent (ELISA) assays, respectively. The effect of PFKP expression on the proliferation of lung cancer cells was assessed using colony forming, MTT and flow cytometry assays, respectively. Finally, data from tissue samples of 533 patients with lung adenocarcinoma and 502 patients with lung squamous cell carcinoma were downloaded from the TCGA database, after which pathway and gene correlation information was retrieved using gene set enrichment analyses.
RESULTS: We found that PFKP was highly expressed in lung cancer tissues and cell lines. Using IHC we found that PFKP was highly expressed in primary lung adenocarcinoma tissues and that a high expression was associated with a poor prognosis. Clinical data analysis revealed that the PFKP expression levels correlated with tumor size and patient survival. Lung cancer cell lines with decreased PFKP expression levels showed significant decreases in glucose uptake rates, lactate levels and adenosine triphosphate concentrations. They also exhibited significantly decreased proliferation rates, colony forming abilities and increased G2/M cell cycle phase percentages. Gene set enrichment analysis revealed that multiple pathways, including glycolytic pathways, may be involved in the regulation PFKP.
CONCLUSIONS: Our data indicate that PFKP is highly expressed in lung cancer tissues and cell lines and is associated with tumor size and patient prognosis. As such, PFKP may serve as a prognostic biomarker. We also found that PFKP regulates the level of glycolysis in lung cancer cells and is associated with lung cancer cell proliferation. These data may be instrumental for the design of new lung cancer treatment options.

Keywords: Cell proliferation; Glycolysis; Lung cancer; PKFP; Warburg effect

DOI: https://doi.org/10.1007/s13402-020-00508-6

Oxid Med Cell Longev. 2020 ;2020 7370157

Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma.

He Du, Bi Chen, Nan-Lin Jiao, Yan-Hua Liu, San-Yuan Sun, You-Wei Zhang.

The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.

DOI: https://doi.org/10.1155/2020/7370157

Nat Cell Biol. 2020 Mar 16.

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.

Tiffany Tsang, Jessica M Posimo, Andrea A Gudiel, Michelle Cicchini, David M Feldser, Donita C Brady.

Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRASG12D is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.

DOI: https://doi.org/10.1038/s41556-020-0481-4

Lung Cancer. 2020 Mar 05. pii: S0169-5002(20)30319-6. [Epub ahead of print]143 19-26

Cachexia - sarcopenia as a determinant of disease control rate and survival in non-small lung cancer patients receiving immune-checkpoint inhibitors.

Benoît Roch, Amandine Coffy, Sandy Jean-Baptiste, Estelle Palaysi, Jean-Pierre Daures, Jean-Louis Pujol, Sébastien Bommart.

PURPOSE: The metabolic changes associated with cachexia - sarcopenia syndrome might down-regulate antitumor immunity. We hypothesized that this syndrome reduces efficiency of immune checkpoint inhibitors (ICPI) in non-small cell lung cancer (NSCLC).
METHODS: The records of 142 consecutive NSCLC patients receiving first- or second-line anti-Programmed cell death protein 1) ICPI were reviewed. Response evaluation according to Response Evaluation Criteria in Solid Tumors 1.1 was performed at the eighth week of immunotherapy. Pretreatment cachexia was defined as a body-weight loss of 5% or more in the previous 6 months. Sarcopenia was estimated with the third lumbar skeletal muscle mass index (mSMI) and was evaluated before immunotherapy and at the eighth week. A decrease by 5% or more of the mSMI was considered as an evolving sarcopenia. The endpoints were disease control rate (DCR), progression-free (PFS) and overall survival (OS).Logistic regression model and Cox model took into account others covariables known to influence ICPI efficiency, particularly Programmed Death -Ligand 1 tumor cell score, Eastern Cooperative Oncology Group performance status and common somatic mutational status.
RESULTS: In multivariate analysis, cachexia - sarcopenia syndrome reduced the probability of achieving a disease control and were associated with a shorter survival. Patients without cachexia had a better probability to achieve disease control in comparison with those who did not experience cachexia (59.9 % and 41.1 %, respectively; odds ratio 95 % (confidence interval [95 %CI]): 2.60 (1.03-6.58)). Patients with cachexia had a shorter OS when compared with those without cachexia (hazard ratios [HR] (95 %CI): 6.26 (2.23-17.57)). Patients with an evolving sarcopenia had a shorter PFS and OS, with HR (95 %CI): 2.45 (1.09-5.53) and 3.87 (1.60-9.34) respectively.
CONCLUSION: Cachexia - sarcopenia syndrome negatively influences patients' outcome during anti-PD-1 ICPI therapy.

Keywords: Anti-PD-(L)1 antibodies; Cachexia; Immune checkpoint inhibitors; Immunotherapy; Lung cancer; NSCLC; Sarcopenia

DOI: https://doi.org/10.1016/j.lungcan.2020.03.003