bims-meluca 2022-03-20 papers

J Cell Mol Med. 2022 Mar 13.

ANGPTL4 regulate glutamine metabolism and fatty acid oxidation in nonsmall cell lung cancer cells.

Song Xiao, Wang Nai-Dong, Yan Jin-Xiang, Tian Long, Lu Xiu-Rong, Gao Hong, Yan Jie-Cheng, Zhang Fei.

Angiopoietin-like protein (ANGPTL) 4 is a key factor in the regulation of lipid and glucose metabolism in metabolic diseases. ANGPTL4 is highly expressed in various cancers, but the regulation of energy metabolism in tumours remains to be determined. This study explored the role of ANGPTL4 in aerobic glycolysis, glutamine consumption and fatty acid oxidation in nonsmall cell lung cancer (NSCLC) cells. Two NSCLC cell lines (A549 and H1299) were used to investigate the role of ANGPTL4 in energy metabolism by tracer techniques and with Seahorse XF technology in ANGPTLs4 knockdown cells. RNA microarrays and specific inhibitors were used to identify targets in ANGPTLs4-overexpressing cells. The results showed that knockdown of ANGPTLs4 could inhibit energy metabolism and proliferation in NSCLC. ANGPTLs4 had no significant effect on glycolysis but affected glutamine consumption and fatty acid oxidation. Knockdown of ANGPTLs4 also significantly inhibited tumour metastasis and energy metabolism in mice and had a weak effect on glycolysis. RNA microarray analysis showed that ANGPTLs4 significantly affected glutaminase (GLS) and carnitine palmitoyl transferase 1 (CPT1). ANGPTLs4-overexpressing cells were exposed to a glutamine deprivation environment, and cell proliferation and energy metabolism were significantly decreased but still differed from normal NSCLC cells. Treatment of ANGPTLs4-overexpressing cells with GLS and CPT1 inhibitors simultaneously prevented the regulatory effects on cell proliferation and energy metabolism. ANGPTLs4 could promote glutamine consumption and fatty acid oxidation but not glycolysis or accelerate energy metabolism in NSCLC.

Keywords: ANGPTL4; NSCLC; aerobic glycolysis; fatty acid oxidation; glutamine

DOI: https://doi.org/10.1111/jcmm.16879

Front Cell Dev Biol. 2022 ;10 730132

A Novel Signature of Lipid Metabolism-Related Gene Predicts Prognosis and Response to Immunotherapy in Lung Adenocarcinoma.

Kai Zhang, Ying Qian, Xiaowei Quan, Tengteng Zhu, Biyun Qian.

Background: Lipid metabolism disorder, a new hallmark of cancer initiation, has been involved in lung adenocarcinoma (LUAD). However, few biomarkers about lipid metabolism-related genes (LMRGs) have been developed for prognosis prediction and clinical treatment of LUAD patients. Methods: In this study, we constructed and validated an effective prognostic prediction model for LUAD patients depending on LMRGs. Subsequently, we investigated the prediction model from immune microenvironment, genomic changes, and immunotherapy. Results: Then, eleven LMRGs were identified and applied to LUAD subtyping. In comparison with the high-risk group, the low-risk group exhibited a remarkably favorable prognosis, along with a higher immune score and lower tumor purity. Moreover, the low-risk group presented higher levels of immune checkpoint molecules, lower tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB), and higher likelihood of benefiting from immunotherapy. Furthermore, the genomic changes of six LMRGs (CD79A, HACD1, CYP17A1, SLCO1B3, ANGPTL4, and LDHA) were responsible for the difference in susceptibility to LUAD by greatly influencing B-cell activation. Conclusion: Generally speaking, the LMRG model is a reliable independent biomarker for predicting adverse outcomes in LUAD patients and has the potential to facilitate risk-stratified immunotherapy.

Keywords: immune checkpoint; immunotherapy; lipid metabolism; lung adenocarcinoma; prognosis model; tumor microenvironment

DOI: https://doi.org/10.3389/fcell.2022.730132

J Cachexia Sarcopenia Muscle. 2022 Mar 18.

The association between skeletal muscle measures and chemotherapy-induced toxicity in non-small cell lung cancer patients.

Corine de Jong, Najiba Chargi, Gerarda J M Herder, Simone W A van Haarlem, Femke van der Meer, Anne S R van Lindert, Alexandra Ten Heuvel, Jan Brouwer, Pim A de Jong, Lot A Devriese, Alwin D R Huitema, Toine C G Egberts, Remco de Bree, Vera H M Deneer.

BACKGROUND: Chemotherapy-induced toxicities frequently occur in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy-induced toxicity in a large cohort of NSCLC patients.
METHODS: A multicentre prospective follow-up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m2 ) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy-induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non-haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose-limiting toxicity (DLT) (treatment switch, delay, de-escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI).
RESULTS: In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non-haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31-4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07-2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non-haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23-4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23-0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT.
CONCLUSIONS: Non-small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.

Keywords: Body composition; Chemotherapy-induced toxicity; Non-small cell lung cancer; Platinum-based chemotherapy; Skeletal muscle mass

DOI: https://doi.org/10.1002/jcsm.12967

Transl Oncol. 2022 Mar 12. pii: S1936-5233(22)00055-9. [Epub ahead of print]19 101393

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling.

Wei-Jing Gong, Peng Cao, Qi-Lin Zhang, Xiao-Yu Han, Shuo-Wen Wang, Yi-Fei Huang, San-Lan Wu, Qiang Li, Rui Zhang, Shuang-Bing Xu, Ya-Ni Liu, Shao-Jun Shi, Yu Zhang.

BACKGROUND: Pemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling.
METHODS: A total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models.
RESULTS: 157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186.
CONCLUSIONS: This study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.

Keywords: Lung adenocarcinoma; Metabolomics; Pemetrexed plus platinum; Prediction model

DOI: https://doi.org/10.1016/j.tranon.2022.101393

Cell Commun Signal. 2022 Mar 15. 20(1): 32

Glycogen synthase kinase GSK3α promotes tumorigenesis by activating HIF1/VEGFA signaling pathway in NSCLC tumor.

Xiaonian Cao, Wei Wu, Dao Wang, Wei Sun, Senyan Lai.

BACKGROUND: Lung cancer is one of the most common cancers and the leading cause of cancer-related death. Glycogen synthase kinase-3 (GSK-3) α, a member of the glycogen synthase kinase-3 family, reportedly plays a role in tumorigenesis. However, its biological function in tumorigenesis requires deeper exploration. Hypoxia is a major feature of solid tumor, along with decreasing availability of oxygen, inducing treatment resistance, and tumor progress.
METHODS: Levels of GSK3α expression in clinical samples were detected using western blot and IHC assays, while its biological function and underlying mechanism of action in tumor progression were investigated using western blot, CCK8, cell cycle, colony formation, Transwell, ELISA and tube formation assays. Furthermore, we investigated the relationship between GSK3α expression and the HIF1α/VEGFA signaling pathway in vivo using a mouse xenograft model.
RESULTS: GSK3α was significantly upregulated in NSCLC patients with cases that exhibited high GSK3α levels recording shorter survival times. Moreover, GSK3α overexpression promoted proliferation, migration, invasion and clone formation ability of NSCLC cells, while its silencing resulted in an opposite phenomenon. Moreover, GSK3α not only activated the HIF1α/VEGFA signaling pathway, but also regulated HIF1α stabilization independently via the PHDs-pVHL signaling pathway. Moreover, GSK3α-mediated tumor angiogenesis depended on HIF1α expression both in vitro and in vivo.
CONCLUSION: GSK3α functioned as an oncogene in NSCLC tumorigenesis by regulating the HIF1/VEGFA signaling pathway in an independent manner through the PHDs-pVHL signaling pathway. These findings were expected to provide novel sights to guide future development of therapies for effective treatment of NSCLC. Video abstract.

Keywords: GSK3α; HIF1α; Tumor angiogenesis

DOI: https://doi.org/10.1186/s12964-022-00825-3