bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2021‒10‒17
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Heme sequestration effectively suppresses the development and progression of both lung adenocarcinoma and squamous cell carcinoma.
  2. AL355338 acts as an oncogenic lncRNA by interacting with protein ENO1 to regulate EGFR/AKT pathway in NSCLC.
  3. Enhanced vulnerability of LKB1-deficient NSCLC to disruption of ATP pools and redox homeostasis by 8-Cl-Ado.
  4. Biomarkers related to fatty acid oxidative capacity are predictive for continued weight loss in cachectic cancer patients.
  5. Neutrophils correlate with hypoxia microenvironment and promote progression of non-small-cell lung cancer.
  6. FV-429 enhances the efficacy of paclitaxel in NSCLC by reprogramming HIF-1α-modulated FattyAcid metabolism.
  7. Proteomic analysis of lung cancer cells reveals a critical role of BCAT1 in cancer cell metastasis.
  1. Mol Cancer Res. 2021 Oct 11. pii: molcanres.0385.2021. [Epub ahead of print]
    Heme sequestration effectively suppresses the development and progression of both lung adenocarcinoma and squamous cell carcinoma.
    Sanchareeka Dey, Adnin Ashrafi, Chantal Vidal, Nivesh Jain, Sarada Preeta Kalainayakan, Poorva Ghosh, Parinaz Sadat Alemi, Narges Salamat, Purna Chaitanya Konduri, Jung-Whan Kim, Li Zhang.
      Lung adenocarcinoma and squamous cell carcinoma are two most common subtypes of lung cancer. Here, to identify new, targetable molecular properties of both subtypes, we monitored changes in the levels of heme- and oxidative phosphorylation (OXPHOS)-related proteins during lung tumorigenesis. Heme is a central molecule for oxidative metabolism and ATP generation via OXPHOS. Notably, both lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors can be induced in the genetically engineered KLLuc mouse model harboring the G12D Kras mutation and a conditional Lkb1 knockout. We found that the levels of the rate-limiting heme synthesis enzyme ALAS1 and uptake protein SLC48A1, along with oxidative phosphorylation (OXPHOS) complex subunits, progressively increased as lung tumorigenesis advanced. Our data demonstrated that elevated levels of heme- and OXPHOS-related proteins were associated with both ADC and SCC. Importantly, treatment of KLLuc mice with a heme-sequestering protein HeSP2 that inhibits heme uptake in tumor cells effectively arrested lung tumor progression, and both ADC and SCC tumors were strongly suppressed. Additionally, HeSP2 effectively suppressed the growth of both SCC and ADC tumor xenografts in NOD/SCID mice. Further analyses indicated that HeSP2 effectively diminished OXPHOS in both ADC and SCC, reduced angiogenesis, alleviated tumor hypoxia, and suppressed cell proliferation. These results show that the advancing of lung tumorigenesis requires progressive increase in cellular heme synthesis and uptake, leading to intensified OXPHOS activity and ATP generation and promoting aggressive tumorigenic functions. Implications: Heme sequestration is an effective strategy for the suppression of both ADC and SCC tumor initiation and development.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0385
  2. Cancer Cell Int. 2021 Oct 09. 21(1): 525
    AL355338 acts as an oncogenic lncRNA by interacting with protein ENO1 to regulate EGFR/AKT pathway in NSCLC.
    Qian Hua, Dongliang Wang, Lin Zhao, Zhihui Hong, Kairu Ni, Yizhen Shi, Zengli Liu, Baoming Mi.
      BACKGROUND: Non-small cell lung cancer (NSCLC) is a malignancy with considerable morbidity and mortality. Abnormal metabolism is a hallmark of cancer; however, the mechanism of glycolysis regulation in NSCLC progression is not completely understood. Recent studies suggest that some dysregulated long non-coding RNAs (lncRNAs) play important roles in tumor metabolic reprogramming.METHODS: To identify glycolysis-associated-lncRNAs in NSCLC, we compared RNA-sequencing results between high 18F-fluorodeoxyglucose (FDG)-uptake NSCLC tissues and paired paratumor tissues. The transcript abundance of AL355338 in 80 pairs of clinical samples was evaluated by quantitative real-time PCR assay and fluorescence in situ hybridization. The biological role of AL355338 on NSCLC cells were evaluated by functional experiments in vitro and in vivo. Moreover, RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the protein interacted with AL355338. Co-immunoprecipitation, in situ proximity ligation assays and western blotting were applied to define the potential downstream pathways of AL355338.
    RESULTS: AL355338 was an upregulated glycolysis-associated lncRNA in NSCLC. Functional assays revealed that AL355338 was critical for promoting aerobic glycolysis and NSCLC progression. Mechanistic investigations showed that AL355338 directly bound with alpha-enolase (ENO1) and enhanced the protein's stability by modulating its degradation and ubiquitination. A positive correlation was observed between AL355338 and ENO1 in NSCLC, and ENO1 was subsequently confirmed to be responsible for the oncogenic role of AL355338. Furthermore, AL355338 was capable of modulating ENO1/EGFR complex interaction and further activating EGFR-AKT signaling.
    CONCLUSIONS: This study indicates that AL355338 confers an aggressive phenotype to NSCLC, and targeting it might be an effective therapeutic strategy.
    Keywords:  AL355338; Aerobic glycolysis; EGFR; ENO1; Long noncoding RNAs
    DOI:  https://doi.org/10.1186/s12935-021-02232-z
  3. Mol Cancer Res. 2021 Oct 15. pii: molcanres.0448.2021. [Epub ahead of print]
    Enhanced vulnerability of LKB1-deficient NSCLC to disruption of ATP pools and redox homeostasis by 8-Cl-Ado.
    Ana Galan-Cobo, Christine M Stellrecht, Emrullah Yilmaz, Chao Yang, Yu Qian, Xiao Qu, Ishita Akhter, Mary L Ayres, Youhong Fan, Pan Tong, Lixia Diao, Jie Ding, Uma Giri, Jayanthi Gudikote, Monique Nilsson, William G Wierda, Jing Wang, Ferdinandos Skoulidis, John D Minna, Varsha Gandhi, John V Heymach.
      Loss of function somatic mutations of STK11, a tumor suppressor gene encoding LKB1 that contributes to the altered metabolic phenotype of cancer cells, is the second most common event in lung adenocarcinomas and often co-occurs with activating KRAS mutations. Tumor cells lacking LKB1 display an aggressive phenotype, with uncontrolled cell growth and higher energetic and redox stress due to its failure to balance ATP and NADPH levels in response to cellular stimulus. The identification of effective therapeutic regimens for LKB1-deficient non-small cell lung cancer (NSCLC) patients remains a major clinical need. Here, we report that LKB1-deficient NSCLC tumor cells displayed reduced basal levels of ATP and to a lesser extent other nucleotides, and markedly enhanced sensitivity to 8-Cl-adenosine (8-Cl-Ado), an energy-depleting nucleoside analogue. Treatment with 8-Cl-Ado depleted intracellular ATP levels, raised redox stress and induced cell death leading to a compensatory suppression of mTOR signaling in LKB1-intact, but not LKB1-deficient, cells. Proteomic analysis revealed that the MAPK/MEK/ERK and PI3K/AKT pathways were activated in response to 8-Cl-Ado treatment and targeting these pathways enhanced the anti-tumor efficacy of 8-Cl-Ado. Implications: Together, our findings demonstrate that LKB1-deficient tumor cells are selectively sensitive to 8-Cl-Ado and suggest that therapeutic approaches targeting vulnerable energy stores combined with signaling pathway inhibitors merit further investigation for this patient population.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0448
  4. J Cachexia Sarcopenia Muscle. 2021 Oct 11.
    Biomarkers related to fatty acid oxidative capacity are predictive for continued weight loss in cachectic cancer patients.
    Silvia Catanese, Carl Friedrich Beuchel, Teresa Sawall, Florian Lordick, Rommy Brauer, Markus Scholz, Uta Ceglarek, Ulrich T Hacker.
      BACKGROUND: Cachexia is characterized by a negative protein and energy balance leading to loss of adipose tissue and muscle mass. Cancer cachexia negatively impacts treatment tolerability and prognosis. Supportive interventions should be initiated as early as possible. Biomarkers for early prediction of continuing weight loss during the course of disease are currently lacking.METHODS: In this pilot, observational, cross-sectional, case-control study, cachectic cancer patients undergoing systemic first-line cancer treatment were matched 2:1 with healthy controls according to age, gender and body mass index. Alterations in amino acid and energy metabolism, as indicated by acylcarnitine levels, were analysed using mass spectrometry in plasma samples (PS) and dried blood specimen (DBS). Welch's two-sample t-test was used for comparative analysis of metabolites between cancer patients and healthy matched controls and to identify the metabolomic profiles related to weight loss across different time points. A linear regression model was applied to correlate weight loss and single metabolites as predictor variables. Finally, metabolite pathway enrichment analyses were performed.
    RESULTS: Eighteen cases (14 male and 4 female) and 36 paired controls were enrolled. There was a good correlation between baseline PS and DBS of healthy controls for the levels of most amino acids but not for acylcarnitine. Amino acid levels related to cancer metabolism were significantly altered in cancer patients compared with controls in both DBS and PS for arginine, citrulline, histidine and ornithine and in DBS only for asparagine, glutamine, methylhistidine, methionine, ornithine, serine, threonine and leucine/isoleucine. Metabolite enrichment analysis in PS of cancer patients revealed histidine metabolism activation (P = 0.0025). Baseline acylcarnitine analysis in DBS was indicative for alterations of the mitochondrial carnitine shuttle, related to β-oxidation: The ratio palmitoylcarnitine/acylcarnitine (Q2) and the ratio palmitoylcarnitine + octadecenoylcarnitine/acylcarnitine (Q3) were predictive for early weight loss (P < 0.0001) and weight loss during follow-up. Activation of tryptophan metabolism (P = 0.035) in DBS and PS and activation of serine/glycine metabolism (P = 0.017) in PS were also related to early weight loss and across successive time points.
    CONCLUSIONS: We found alterations in amino acid levels most likely attributable to cancer metabolism itself in cancer patients compared with controls. Baseline DBS represent a valuable analyte to study energy metabolism related to cancer cachexia. Acylcarnitine patterns (Q2, Q3) predicted further weight loss in cachectic cancer patients undergoing systemic therapy, and pathway analyses indicated involvement of the serine/glycine and the tryptophan pathway in this condition. Validation in larger cohorts is warranted.
    Keywords:  Biomarkers; Cachexia; Cancer; Mass spectrometry; Metabolomics; Weight loss
    DOI:  https://doi.org/10.1002/jcsm.12817
  5. Bioengineered. 2021 Oct 12.
    Neutrophils correlate with hypoxia microenvironment and promote progression of non-small-cell lung cancer.
    Chunyan Zhang, Bingxiang Tang, Jianping Hu, Xiang Fang, Hongzhi Bian, Junlei Han, Congxia Hou, Fang Sun.
      Hypoxia, a strong and selective pressure, has been involved in invasion, metastasis, and angiogenesis of tumor cells. Our study performed the transcriptome profiles of 666 non-small-cell lung cancer (NSCLC) patients. Various bioinformatic approaches were combined to evaluate the immune cell infiltration in the high hypoxia risk patients. In addition, in vitro experiments were performed to assess the effects of tumor-associated neutrophils (TANs) on NSCLC cells proliferation, migration and invasion and to reveal the underlying mechanisms. We divided NSCLC into two groups (Cluster1/2) based on the expression profiles of hypoxia-associated genes. Compared with the Cluster1 subgroup, the Cluster2 had a worse prognosis. Significant enrichment analysis revealed that PI3K/AKT/mTOR signaling pathway and TANs were highly related to hypoxia microenvironment. Eleven hypoxia-related genes (FBP1, NDST2, ADM, LDHA, DDIT4, EXT1, BCAN, IGFBP1, PDGFB, AKAP12, and CDKN3) were scored by LASSO COX regression to yield risk scores, and we revealed a significant difference in overall survival (OS) between the low- and high-risk groups. Mechanistically, CXCL6 in hypoxic cancer cells promoted the migration of TANs in vitro, and in turn promote NSCLC cells proliferation, migration and invasion. In summary, this study revealed a 11-hypoxia gene signature that predicted OS of NSCLC patients, and improved our understanding of the role of TANs in hypoxia microenvironment.
    Keywords:  CXCL6; gene signature; hypoxia; non-small-cell lung cancer; progression; tumor-associated neutrophils
    DOI:  https://doi.org/10.1080/21655979.2021.1987820
  6. Chem Biol Interact. 2021 Oct 11. pii: S0009-2797(21)00340-9. [Epub ahead of print] 109702
    FV-429 enhances the efficacy of paclitaxel in NSCLC by reprogramming HIF-1α-modulated FattyAcid metabolism.
    Yongjian Guo, Liliang Yang, Wenjing Guo, Libin Wei, Yuxin Zhou.
      Solid tumors often exhibit hypoxia in their centers, which has been associated with a marked reduction in the sensitivity of the tumor cells to anti-tumor and chemotherapeutic interventions. Here, we found that the occurrence and progress of hypoxic insensitivity to paclitaxel in non-small cell lung cancer (NSCLC) are closely associated with the HIF-1α pathway. The HIF-1α protein upregulated the expression of adipose differentiation-related protein (ADRP), fatty acid synthase (FASN), and sterol regulatory element binding protein 1(SREBP1), while simultaneously downregulating carnitine palmitoyltransferase 1 (CPT1), thereby leading to a more pronounced uptake of lipids and reduced oxidation of fatty acids. Diminished levels of fatty acids led to reduced Wnt pathway activation and β-catenin nuclear translocation, leading to G2/M cell cycle arrest. In this study, FV-429, a derivative of the natural flavonoid wogonin, reprogrammed metabolism of cancer cells and decreased fatty acid levels. Moreover, paclitaxel-induced G2/M phase arrest in hypoxia-resistant NSCLC was hampered but FV-429 improved the sensitivity of these cancer cells to paclitaxel. FV-429 activated and modulated fatty acid metabolism in NSCLC cells, significantly reduced levels of fatty acids within cells and increased the oxidation of these fatty acids. The results of our study demonstrated that FV-429 could reshape fatty acid metabolism in hypoxia-induced paclitaxel-resistant NSCLC and enhance the sensitivity of NSCLC cells to paclitaxel through G2/M phase arrest deterioration, by inactivating the Wnt pathway, and suggested the possibility of using FV-429 as a promising candidate therapeutic agent for advanced NSCLC.
    Keywords:  FV-429; Fatty acid; HIF-1α; NSCLC; β-catenin
    DOI:  https://doi.org/10.1016/j.cbi.2021.109702
  7. Theranostics. 2021 ;11(19): 9705-9720
    Proteomic analysis of lung cancer cells reveals a critical role of BCAT1 in cancer cell metastasis.
    Lin Mao, Jin Chen, Xue Lu, Canlin Yang, Yi Ding, Mingming Wang, Yunpeng Zhang, Yuying Tian, Xing Li, Yunyun Fu, Yueying Yang, Yunyun Gu, Fei Gao, Junxing Huang, Lujian Liao.
      Metastasis is the major cause of high mortality in lung cancer. Exploring the underlying mechanisms of metastasis thus holds promise for identifying new therapeutic strategies that may enhance survival. Methods: We applied quantitative mass spectrometry to compare protein expression profiles between primary and metastatic lung cancer cells whilst investigating metastasis-related molecular features. Results: We discovered that BCAT1, the key enzyme in branched-chain amino acid metabolism, is overexpressed at the protein level in metastatic lung cancer cells, as well as in metastatic tissues from lung cancer patients. Analysis of transcriptomic data available in the TCGA database revealed that increased BCAT1 transcription is associated with poor overall survival of lung cancer patients. In accord with a critical role in metastasis, shRNA-mediated knockdown of BCAT1 expression reduced migration of metastatic cells in vitro and the metastasis of these cells to distal organs in nude mice. Mechanistically, high levels of BCAT1 depleted α-ketoglutarate (α-KG) and promoted expression of SOX2, a transcription factor regulating cancer cell stemness and metastasis. Conclusion: Our findings suggest that BCAT1 plays an important role in promoting lung cancer cell metastasis, and may define a novel pathway to target as an anti-metastatic therapy.
    Keywords:  BCAT1; SOX2; metastasis; stemness
    DOI:  https://doi.org/10.7150/thno.61731
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