bims-meluca 2020-08-09 papers

Cancer Sci. 2020 Aug 07.

DRP1 promotes lactate utilization in KRAS-mutant non-small cell lung cancer cells.

Mangze Hu, Yu Zhao, Yuejiao Cao, Qianru Tang, Ziqin Feng, Jun Ni, Xiaorong Zhou.

Metabolic alterations are well documented in various cancers. Non-small cell lung cancers (NSCLCs) preferentially use lactate as the primary carbon source, but the underlying mechanisms are not well understood. We developed a lactate-dependent cell proliferation assay and found that dynamin-related protein (DRP1), which is highly expressed in KRAS-mutant NSCLC, is required for tumor cells to proliferate and uses lactate as fuel, demonstrating the critical role of DRP1 in the metabolic reprogramming of NSCLC. Metabolic and transcriptional profiling suggests that DRP1 orchestrates a supportive metabolic network to promote lactate utilization and redox homeostasis in lung cancer cells. DRP1 suppresses the production of reactive oxygen species (ROS) and protects cells against oxidative damage by enhancing lactate utilization. Moreover, targeting DRP1 not only reduces HSP90 expression but also enhances ROS-induced HSP90 cleavage, thus inhibiting activation of the MAPK and PI3K pathways and leading to suppressed lactate utilization and increased ROS-induced cell death. Taken together, these results suggest that DRP1 is a crucial regulator of lactate metabolism and redox homeostasis in KRAS-mutant lung cancer, and targeting lactate utilization by modulating DRP1 activity might be an effective treatment for lung cancer.

Keywords: Cancer metabolism; DRP1; KRAS mutation; Lactate; Lung cancer

DOI: https://doi.org/10.1111/cas.14603

J Lipid Res. 2020 Aug 04. pii: jlr.RA120000899. [Epub ahead of print]

Myc linked to dysregulation of cholesterol transport and storage in non-small cell lung cancer.

Zoe Hall, Catherine H Wilson, Deborah L Burkhart, Tom Ashmore, Gerard I Evan, Julian L Griffin.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Whilst mutations in Kras and over-expression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc, in combination with surface analysis lipid profiling of lung tumours and transcriptomics, to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that activation of Myc leads to the accumulation of cholesteryl esters (CE), stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumours in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux and accumulation of CE-rich lipid droplets in lung tumours. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.

Keywords: Cancer; Cholesterol; Lipidomics; Lung; Mass spectrometry; adenocarcinoma; cholesteryl ester; lipid metabolism; liquid extraction surface analysis; mass spectrometry

DOI: https://doi.org/10.1194/jlr.RA120000899

Nutr Cancer. 2020 Aug 04. 1-8

The Effect of Body Mass Index on Treatment Outcomes in Patients with Metastatic Non-Small Cell Lung Cancer Treated with Platinum-Based Therapy.

Aysegul Sakin, Suleyman Sahin, Muhammed Mustafa Atci, Nurgul Yasar, Cumhur Demir, Caglayan Geredeli, Abdullah Sakin, Sener Cihan.

To investigate the effect of body mass index(BMI) on treatment outcomes and side-effect profile in metastatic non-small cell lung cancer(NSCLC) patients receiving platinum-based chemotherapy(ChT) in the first-line setting. This was a retrospective analysis of 233 NSCLC patients who were treated and followed up from 2008 through 2018. NSCLC patients who had metastatic disease at the time of diagnosis and were treated with platinum-based ChT in the first-line setting were included. The patients were divided into 2 groups based on the BMI as follows; BMI < 25 kg/m2 and BMI ≥ 25 kg/m2. This retrospective analysis enrolled 233 patients, 35 (15.0%) of whom were female. The BMI in 132 patients (56.2%) was < 25 kg/m2. The median age was 58 years (range, 21-90). Median progression-free survival(PFS) was 7 mo, in the patients with BMI ≥ 25 kg/m2 compared to 5.0 mo, in those with BMI < 25 kg/m2 (p = 0.032), with corresponding median overall survival(OS) durations of 12 vs. 9 mo, (p = 0.003). In multivariate analysis, ECOG PS 2, grade III histology, and brain or bone metastasis negatively affected OS, whereas BMI ≥ 25 kg/m2 positively affected OS. A high BMI prior to therapy in patients with NSCLC treated with platinum-based ChT in the first-line setting was associated with more favorable PFS and OS.

DOI: https://doi.org/10.1080/01635581.2020.1801774