bims-meluca 2021-02-28 papers

bims-meluca

Biomed News

on Metabolism of non-small cell lung carcinoma

Issue of 2021‒02‒28
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

Oxidative stress-mediated AMPK inactivation determines the high susceptibility of LKB1-mutant NSCLC cells to glucose starvation.
Comparison of the Effects of Statins on A549 Nonsmall-Cell Lung Cancer Cell Line Lipids Using Fourier Transform Infrared Spectroscopy: Rosuvastatin Stands Out.
Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth.
First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer.
Association of HIF1-α gene polymorphisms with advanced non-small cell lung cancer prognosis in patients receiving radiation therapy.
Blood T cell diversity associated with the prognosis of advanced non-small cell lung carcinoma treated with first-line pemetrexed based chemotherapy.
SLC7A7 is a prognostic biomarker correlated with immune infiltrates in non-small cell lung cancer.

Free Radic Biol Med. 2021 Feb 23. pii: S0891-5849(21)00108-8. [Epub ahead of print]

Oxidative stress-mediated AMPK inactivation determines the high susceptibility of LKB1-mutant NSCLC cells to glucose starvation.

Ren Y, Chen J, Chen P, Hao Q, Cheong LK, Tang M, Hong LL, Hu XY, Celestial T Yap , Bay BH, Ling ZQ, Shen HM.

  The liver kinase B1 (LKB1) is an important tumor suppressor and its loss-of-function mutations are observed in around 16% of non-small cell lung cancer (NSCLC) cases. One of the main functions of LKB1 is to activate AMP-activated protein kinase (AMPK) via direct phosphorylation. Under metabolic or energy stress conditions, the LKB1-AMPK axis inhibits the anabolic pathways and activates the catabolic pathways to maintain metabolic homeostasis for cell survival. In this study, we found that LKB1-mutant NSCLC cells are particularly susceptible to cell death induced by glucose starvation, but not by other forms of starvation such as amino acid starvation or serum starvation. Reconstitution of LKB1 in LKB1-mutant cells or LKB1 knockout in LKB1-wild type cells highlighted the importance of the LKB1-AMPK axis for cell survival under glucose starvation. Mechanistically, in LKB1-mutant cells, glucose starvation elicits oxidative stress, which causes AMPK protein oxidation and inactivation, and eventually cell death. Importantly, this process could be effectively reversed and rescued by 2DG (a glucose analog capable of producing NADPH, a key antioxidant), A769662 (an allosteric AMPK activator), and N-acetyl cysteine (NAC) (a ROS scavenger), indicating the presence of a vicious circle between AMPK inactivation and ROS in LKB1-mutant NSCLC cells under glucose starvation. Our study thus elucidates the critical role of redox balance in determining the susceptibility to cell death under glucose starvation in LKB1-mutant NSCLC cells. The findings from this study reveal important clues in search of novel therapeutic strategies for LKB1-mutant NSCLC by targeting glucose metabolism and redox balance.

Keywords:  AMP-activated protein kinase; glucose starvation; liver kinase B1; non-small cell lung cancer; reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.02.018
Lipids. 2021 Feb 21.

Comparison of the Effects of Statins on A549 Nonsmall-Cell Lung Cancer Cell Line Lipids Using Fourier Transform Infrared Spectroscopy: Rosuvastatin Stands Out.

Aksoy HN, Ceylan C.

  Statins are commonly prescribed antilipidemic and anticholesterol class of drugs. In addition to their major role, they have been found to have anticancer effects on in vitro, animal and clinical studies. The aim of this study was to investigate the effects of six different statins (rosuvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, and atorvastatin) on A549 cancer cells lipids by Fourier transform infrared (FTIR) spectroscopy. Proliferation tests were carried out to detect the half-maximal inhibitory concentrations (IC50 ) of each statin on A549 cells. The IC50 values were 50 μM for simvastatin, 150 μM for atorvastatin and pravastatin, and 170 μM for fluvastatin, 200 μM for rosuvastatin and lovastatin on A549 cells. No correlation was found between the antiproliferative effects of the statins and lipid-lowering effect. The cells were treated with IC5 , IC10 , and IC50 values of each statins concentration and lipid extracts were compared using FTIR spectroscopy. The results indicated that different statins had different effects on the lipid content of A549 cells. The FTIR spectra of the lipid exctracts of statin-treated A549 cells indicated that the value of hydrocarbon chain length, unsaturation index, oxidative stress level, and phospholipid containing lipids increased except for rosuvastatin-treated A549 cells. In addition, rosuvastatin significantly lowered cholesterol ester levels. In conclusion, the contrasting effects of rosuvastatin should be further investigated.

Keywords:  A549; FTIR; Lipid; Nonsmall-cell lung cancer; Rosuvastatin; Statin

DOI:  https://doi.org/10.1002/lipd.12296
Cell Metab. 2021 Feb 17. pii: S1550-4131(21)00057-7. [Epub ahead of print]

Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth.

Krall AS, Mullen PJ, Surjono F, Momcilovic M, Schmid EW, Halbrook CJ, Thambundit A, Mittelman SD, Lyssiotis CA, Shackelford DB, Knott SRV, Christofk HR.

  Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.

Keywords:  asparaginase; asparagine; cancer metabolism; cancer treatment; dietary restriction; metformin; respiration

DOI:  https://doi.org/10.1016/j.cmet.2021.02.001
Lung Cancer. 2021 Feb 17. pii: S0169-5002(21)00075-1. [Epub ahead of print]154 99-104

First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer.

Cheng H, Zou Y, Shah CD, Fan N, Bhagat TD, Gucalp R, Kim M, Verma A, Piperdi B, Spivack SD, Halmos B, Perez-Soler R.

  BACKGROUND: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking.PATIENTS AND METHODS: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 μm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy.
RESULTS: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days.
CONCLUSIONS: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions.

Keywords:  Inhaled Azacitidine; Lung cancer

DOI:  https://doi.org/10.1016/j.lungcan.2021.02.015
Aging (Albany NY). 2021 Feb 17. 13

Association of HIF1-α gene polymorphisms with advanced non-small cell lung cancer prognosis in patients receiving radiation therapy.

Zhang Y, Wang J, Li Z.

  We investigated the association between single nucleotide polymorphisms (SNPs) in the HIF1A gene and the prognosis of advanced non-small cell lung cancer (NSCLC) patients undergoing radiation therapy. Patient overall survival (OS) and progression-free survival (PFS) were analyzed. The rs11549465 TT genotype was associated with poor PFS (P<0.001) and OS (P=0.001). The rs2057482 TT genotype was also associated with poor PFS (P=0.002) and OS (P=0.007). Stratified analyses revealed that these associations occurred in patients with a smoking history, squamous cell carcinoma, and stage IIIA disease, as well as those receiving radiation therapy a radiation dose of ≥70 Gy. We found associations between SNPs and PFS but not OS in patients without a smoking history, other histological types, and stage IIIB disease, as well as those undergoing chemoradiotherapy with a radiation dose of <70 Gy. No associations were observed between rs11549467 or rs110873142 and NSCLC prognosis. These results suggest that HIF1A polymorphisms can be used as independent prognostic biomarkers for NSCLC patients receiving radiation therapy.

Keywords:  gene polymorphisms; non-small cell lung cancer; prognosis; survival

DOI:  https://doi.org/10.18632/aging.202542
Thorac Cancer. 2021 Feb 24.

Blood T cell diversity associated with the prognosis of advanced non-small cell lung carcinoma treated with first-line pemetrexed based chemotherapy.

Qian L, Zhaohui Z, Yaping X, Zhentian L, Zhentao L, Qiqi W, Yangchun G, Yan'e L, Wencheng Y, Fumei Y, Yanhong Y, Baoshan C, Li L.

  BACKGROUND: The tumor microenvironment is associated with prognosis in advanced non-small cell lung carcinoma (NSCLC). The aim of this study was to explore the relationship between blood T cell diversity and survival of patients treated with pemetrexed-based chemotherapy for nonsquamous NSCLC.METHODS: This prospective clinical study enrolled 26 patients with advanced NSCLC treated with 4-6 cycles of first-line pemetrexed combined with platinum-based therapy. The complementarity-determining region 3 (CDR3) located in the T cell receptor beta chain (TCR β chain) was captured and deeply sequenced using next-generation sequencing (NGS) technology, and the correlation between TCR changes and efficacy after chemotherapy was analyzed.
RESULTS: Patients with an inferior quarter diversity index showed a significantly shorter progression-free survival (PFS) than the others (median, 5.0 months vs. 8.1 months, P = 0.014). After two cycles of chemotherapy, the TCR diversity was significantly higher than the baseline (P = 0.034). Just as with the baseline, patients with an inferior quarter diversity index at the endpoint of cycle 2 showed a shorter progression-free survival (PFS) than the others (median, 5.0 months vs. 8.4 months, P = 0.024).
CONCLUSIONS: In advanced NSCLC patients treated with first-line pemetrexed combined with platinum, the low level of blood TCR diversity at baseline with an endpoint of two cycles of chemotherapy was correlated with a poor prognosis.

Keywords:  Advanced non-small cell lung carcinoma; T cell diversity; tumor microenvironment

DOI:  https://doi.org/10.1111/1759-7714.13771
Cancer Cell Int. 2021 Feb 15. 21(1): 106

SLC7A7 is a prognostic biomarker correlated with immune infiltrates in non-small cell lung cancer.

Dai W, Feng J, Hu X, Chen Y, Gu Q, Gong W, Feng T, Wu J.

  BACKGROUND: SLC7A7 (solute carrier family 7, amino acid transporter light chain, y + L system, member 7) is a critical gene in the regulation of cationic amino acid transport. However, the relationships between SLC7A7 and prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear.METHODS: SLC7A7 expression was analyzed using the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. The enrichment of the GO (Gene Oncology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways was conducted by DAVID. We evaluated the influence of SLC7A7 on clinical prognosis using the PrognoScan database. The functional state of SLC7A7 in various types of cancers was analyzed by CancerSEA. The relationships between SLC7A7 and cancer immune infiltrates was investigated by TIMER. Furthermore, correlations between SLC7A7 expression and gene marker sets of immune infiltrates were analyzed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). The expression of SLC7A7 was verified by GEO database and immunohistochemistry.
RESULTS: A lung cancer cohort study (GSE31210) showed that high SLC7A7 expression was associated with poor overall survival (OS) and relapse-free survival (RFS). In addition, SLC7A7 had a significant impact on the prognosis of diverse cancers. SLC7A7 expression was positively correlated with infiltrating levels of CD4 + and CD8 + T cells, macrophages, neutrophils and dendritic cells (DCs) in non-small cell lung cancer (NSCLC). SLC7A7 expression was also strongly correlated with various immune marker sets in NSCLC.
CONCLUSIONS: These results indicated a role for SLC7A7 in infiltration of CD8 + T cells, CD4 + T cells, tumor-associated macrophages (TAMs), neutrophils and DCs in multiple cancers, and regulation of T cell exhaustion and Tregs in NSCLC. These findings suggest that SLC7A7 could be served as a biomarker for prognosis and immune infiltration in NSCLC.

Keywords:  Lymphocytes; Non-small cell lung cancer; Prognosis; SLC7A7; Tumor-infiltrating

DOI:  https://doi.org/10.1186/s12935-021-01781-7