bims-meluca 2020-03-15 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–03–15
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Potential of FDG-PET as Prognostic Significance after anti-PD-1 Antibody against Patients with Previously Treated Non-Small Cell Lung Cancer.
TRIM59 knockdown blocks cisplatin resistance in A549/DDP cells through regulating PTEN/AKT/HK2.
CircAKT3 inhibits glycolysis balance in lung cancer cells by regulating miR-516b-5p/STAT3 to inhibit cisplatin sensitivity.
A High-Performing Plasma Metabolite Panel for Early-Stage Lung Cancer Detection.
Predictive value of serum VEGF levels for elderly patients or for patients with poor performance status receiving anti-PD-1 antibody therapy for advanced non-small-cell lung cancer.
Serum lipidomic biomarkers for non-small cell lung cancer in nonsmoking female patients.

J Clin Med. 2020 Mar 07. pii: E725. [Epub ahead of print]9(3):

Potential of FDG-PET as Prognostic Significance after anti-PD-1 Antibody against Patients with Previously Treated Non-Small Cell Lung Cancer.

Kosuke Hashimoto, Kyoichi Kaira, Ou Yamaguchi, Atsuto Mouri, Ayako Shiono, Yu Miura, Yoshitake Murayama, Kunihiko Kobayashi, Hiroshi Kagamu, Ichiei Kuji.

  It remains unclear whether the accumulation of 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) before the initiation of anti-programmed death-1 (PD-1) antibody can predict the outcome after its treatment. The aim of this study is to retrospectively examine the prognostic significance of 18F-FDG uptake as a predictive marker of anti-PD-1 antibody. Eighty-five patients with previously treated non-small cell lung cancer (NSCLC) who underwent 18F-FDG-positron emission tomography (PET) just before administration of nivolumab or pembrolizumab monotherapy were eligible in our study, and metabolic tumor volume (MTV), total lesion glycolysis (TLG) and the maximum of standardized under value (SUVmax) on 18F-FDG uptake were assessed. Objective response rate, median progression-free survival and median overall survival were 36.6%, 161 days and 716 days, respectively. The frequency of any immune-related adverse events was significantly higher in patients with low 18F-FDG uptake on PET than in those with high uptake. By multivariate analysis, the tumor metabolic activity by TLG and MTV was identified as an independent prognostic factor for predicting outcome after anti-PD-1 antibody therapy, but not SUVmax, predominantly in patients with adenocarcinoma. Metabolic tumor indices as TLG and MTV on 18F-FDG uptake could predict the prognosis after anti-PD-1 antibodies in patients with previously treated NSCLC.

Keywords:  FDG-PET; PD-1; immune checkpoint inhibitor; lung cancer; prognosis

DOI:  https://doi.org/10.3390/jcm9030725
Gene. 2020 Mar 09. pii: S0378-1119(20)30222-5. [Epub ahead of print] 144553

TRIM59 knockdown blocks cisplatin resistance in A549/DDP cells through regulating PTEN/AKT/HK2.

Rong He, Hongxu Liu.

  Cisplatin is commonly used for lung cancer treatment. However, acquire resistance to cisplatin results in reduced therapy efficacy. Tripartite motif-containing 59 (TRIM59), acting as an oncogene in non-small cell lung cancer (NSCLC), induces chemoresistance in breast cancer cells. Here, the mechanism by which TRIM59 mediates cisplatin resistance was determined. We demonstrated that cisplatin-resistant NSCLC cell line (A549/DDP) had higher expression of TRIM59 than its parental cell line (A549). As indicated by cell apoptosis assay, TRIM59 overexpression in A549 cells resulted in an increased cisplatin resistance, while TRIM59 downregulation in A549/DDP cells led to an decreased cisplatin resistence. A549/DDP cells with TIMR59 knockdown was more sensitive to cisplatin treatment in a xenograft model. Moreover, A549/DDP cells exhibited increased glucose uptake, lactate production, and hexokinase 2 (HK2, an important glycolytic pathway enzyme) expression than A549 cells. The glycolysis was increased by TRIM59 overexpression in A549 cell, and decreased by TRIM59 knockdown in A549/DDP cells. 3-Bromopyruvate Acid (3-BrPA), an inhibitor of HK2, significantly enhanced cisplatin-sensitivity in A549 cells overexpressing TRIM59. Furthermore, both TRIM59 and HK2 expression was higher in cisplatin-resistant NSCLC tissues than in non-resistant ones, and mRNA expression of these two molecules was positively correlated in NSCLC tissues. The changes of PTEN and phosphorylation of AKT (p-AKT), a critical upstream regulator of HK2, were also consistent with HK2 expression. Immunoprecipiation experiments showed the interaction between TRIM59 and PTEN in A549/DDP cells, and that TRIM59 knockdown suppressed the ubiquitination of PTEN. Collectively, the present study indicates that TRIM59 knockdown reverses high glycolysis rate and cisplatin resistance in A549/DDP cells through the regulation of PTEN/AKT/HK2 and may provide insights into overcoming cancer resistance to cisplatin treatment.

Keywords:  NSCLC; TRIM59; cisplatin resistance; glycolysis

DOI:  https://doi.org/10.1016/j.gene.2020.144553
Biotechnol Lett. 2020 Mar 13.

CircAKT3 inhibits glycolysis balance in lung cancer cells by regulating miR-516b-5p/STAT3 to inhibit cisplatin sensitivity.

Yangling Xu, Tiantian Jiang, Changgang Wu, Yongqing Zhang.

   OBJECTIVE: Lung cancer was one of the most deadly cancers around the world. Circular RNA AKT3 (CircAKT3) was highly expressed in lung cancer and could inhibit cell proliferation, but there were few studies on the mechanism of specific regulation of drug resistance. Therefore, we aimed to provide new ideas and perspectives for the role of circAKT3 in the mechanism of tumor resistance.
METHODS: The levels of circAKT3, miR-516b-5p and STAT3 in lung cancer tissues and cells were examined using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assays. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to examine the sensitivity of cells treated under different conditions to cisplatin (DDP). A glucose assay kit and lactate assay kit were used to assess glycolysis and lactate production of cells treated with different plasmids and 2-deoxy-glucose (2-DG). Western blot analysis was used to detect the expression level of the hypoxia-inducible factor (HIF-1α) in A549 and H1299 cells. Starbase 3.0 predicted a targeted relationship between circAKT3 and miR-516b-5p, STAT3 and miR-516b-5p, and the relationship was proved by a dual-luciferase reporter assay. Knockdown of circAKT3 was used to study the effects of circAKT3 on tumor development in vivo.
RESULTS: The levels of circAKT3 and STAT3 were upregulated, miR-516b-5p was downregulation in lung cancer tissues and cells. Functionally, circAKT3 knockdown improved cell sensitivity to DDP, and repressed glycolysis in lung cancer cells. Meanwhile, inhibition of HIF-1α-dependent glycolysis attenuated the circAKT3-induced increase of chemo-resistance in A549 cells. Mechanistically, miR-516b-5p was found to possess some binding sites with circAKT3. Noticeably, the inhibitory action of circAKT3 knockdown on DDP resistance and glycolysis was overturned through inhibitor of miR-516b-5p in lung cancer cells. Furthermore, besides, circAKT3 knockdown suppressed lung tumor cell growth by the miR-516b-5p/STAT3 axis in vivo.
CONCLUSIONS: CircAKT3 inhibit cisplatin sensitivity of lung cancer cells at least partly through regulating miR-516b-5p/STAT3 axis-mediated glycolysis balance, providing a possible long noncoding RNA -targeted therapy for lung cancer.

Keywords:  Cisplatin; Drug sensitivity; Glycolysis; Lung cancer; STAT3; circAKT3; miR-516b-5p

DOI:  https://doi.org/10.1007/s10529-020-02846-9
Cancers (Basel). 2020 Mar 07. pii: E622. [Epub ahead of print]12(3):

A High-Performing Plasma Metabolite Panel for Early-Stage Lung Cancer Detection.

Lun Zhang, Jiamin Zheng, Rashid Ahmed, Guoyu Huang, Jennifer Reid, Rupasri Mandal, Andrew Maksymuik, Daniel S Sitar, Paramjit S Tappia, Bram Ramjiawan, Philippe Joubert, Alessandro Russo, Christian D Rolfo, David S Wishart.

  The objective of this research is to use metabolomic techniques to discover and validate plasma metabolite biomarkers for the diagnosis of early-stage non-small cell lung cancer (NSCLC). The study included plasma samples from 156 patients with biopsy-confirmed NSCLC along with age and gender-matched plasma samples from 60 healthy controls. A fully quantitative targeted mass spectrometry (MS) analysis (targeting 138 metabolites) was performed on all samples. The sample set was split into a discovery set and validation set. Metabolite concentration data, clinical data, and smoking history were used to determine optimal sets of biomarkers and optimal regression models for identifying different stages of NSCLC using the discovery sets. The same biomarkers and regression models were used and assessed on the validation models. Univariate and multivariate statistical analysis identified β-hydroxybutyric acid, LysoPC 20:3, PC ae C40:6, citric acid, and fumaric acid as being significantly different between healthy controls and stage I/II NSCLC. Robust predictive models with areas under the curve (AUC) > 0.9 were developed and validated using these metabolites and other, easily measured clinical data for detecting different stages of NSCLC. This study successfully identified and validated a simple, high-performing, metabolite-based test for detecting early stage (I/II) NSCLC patients in plasma. While promising, further validation on larger and more diverse cohorts is still required.

Keywords:  LC-MS; cancer staging; early detection; lung cancer; metabolomics

DOI:  https://doi.org/10.3390/cancers12030622
Cancer Immunol Immunother. 2020 Mar 10.

Predictive value of serum VEGF levels for elderly patients or for patients with poor performance status receiving anti-PD-1 antibody therapy for advanced non-small-cell lung cancer.

Ryota Shibaki, Shuji Murakami, Yuki Shinno, Yuji Matsumoto, Tatsuya Yoshida, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Yutaka Fujiwara, Nobuyuki Yamamoto, Noboru Yamamoto, Yuichiro Ohe.

  The efficacy of immune checkpoint inhibitors (ICIs) in elderly and poor performance status (PS) patients is controversial, because clinical evidence is limited. This study aimed to find a predictive biomarker for the efficacy of anti-programmed cell death 1 (PD-1) antibodies in these patient populations. We retrospectively reviewed medical records of advanced non-small-cell lung cancer (NSCLC) patients who were ≥ 75 years of age or classified as PS 2 and received anti-PD-1 antibody treatment between December 2015 and May 2018. We evaluated the association between the efficacy of the anti-PD-1 antibody in these patients and the clinical variables thought to affect ICI efficacy. A total of 235 patients with advanced NSCLC were treated with anti-PD-1 antibodies, among whom 31 patients were ≥ 75 years of age and 22 were PS 2. A Cox proportional hazard model showed that only high levels of serum vascular endothelial growth factor (VEGF) were significantly associated with a shorter progression-free survival in patients aged ≥ 75 years and those with PS 2. Among these cohorts, the overall response rate to anti-PD-1 treatment tended to be lower when serum VEGF was high compared to patients with low serum VEGF. Our results demonstrate that serum VEGF concentration may be a negative predictive biomarker in elderly and poor PS advanced NSCLC patients receiving anti-PD-1 antibody treatment. This finding may help identify patients who will not benefit from anti-PD-1 antibody therapy.

Keywords:  Anti-PD-1 antibody; Elderly; Non-small-cell lung cancer; Performance status; Vascular endothelial growth factor

DOI:  https://doi.org/10.1007/s00262-020-02539-2
J Pharm Biomed Anal. 2020 Feb 29. pii: S0731-7085(19)33002-X. [Epub ahead of print]185 113220

Serum lipidomic biomarkers for non-small cell lung cancer in nonsmoking female patients.

Hamada A A Noreldeen, Lijie Du, Wei Li, Xinyu Liu, Yanfu Wang, Guowang Xu.

  Lung cancer (Lca) is one of the malignant tumors with the fastest morbidity and mortality increase and the greatest threat to human health and life. The incidence of non-small cell lung cancer (NSCLC) in the nonsmoking female has increased recently. However, its pathogenesis is still unclear, and there is an urgent need for clinical diagnostic biomarkers, especially for early diagnosis. A nontargeted lipidomic approach based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS), as well as two machine learning approaches (genetic algorithm and binary logistic regression) was used to screen candidate discriminating lipids and define a combinational lipid biomarker in serum samples to distinguish female patients with NSCLC from healthy controls. Moreover, the candidate biomarkers were verified by using an external validation sample set. Our result revealed that fatty acid (FA) (20:4), FA (22:0) and LPE (20:4) can serve as a combinational biomarker for distinguishing female patients with NSCLC from healthy control with good sensitivity and specificity. Furthermore, this combinational biomarker also showed good performance in distinguishing early-stage NSCLC female patients from a healthy control. We observed that levels of unsaturated fatty acids clearly decreased, while saturated fatty acids and lysophosphatidylethanolamines pronouncedly increased in Lca patients, compared with the healthy controls, which revealed significant disturbance of lipid metabolism in NSCLC females. Our results not only provide hints to the pathological mechanism of NSCLC in nonsmoking female but also supply a combinational lipid biomarker to aid the diagnosis of NSCLC at early-stage.

Keywords:  Early-Stage biomarker; Lipidomics; Liquid chromatography−mass spectrometry; Non-Small cell lung cancer; Nonsmoking female

DOI:  https://doi.org/10.1016/j.jpba.2020.113220