bims-meluca Biomed news
on Metabolism of non-small cell lung carcinoma
Issue of 2018‒09‒16
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Phytomedicine. 2018 Sep 15. pii: S0944-7113(18)30150-8. [Epub ahead of print]48 51-61
    Zhang W, Shi H, Chen C, Ren K, Xu Y, Liu X, He L.
      BACKGROUND: Curcumin is a naturally occurring polyphenol which has been demonstrated to possess diverse biological activities. We previously reported that curcumin is a biologically active copper chelator with antitumor activity. Copper transporter 1 (CTR1) on the plasma membrane of eukaryotic cells mediates both copper as well as anticancer drug cisplatin uptake.PURPOSE: This study aims to investigate whether curcumin enhances cisplatin sensitivity of human non-small cell lung cancer (NSCLC) through influencing Cu-Sp1-CTR1 regulatory loop.
    METHODS: The combination effect of curcumin and cisplatin on cell proliferation and apoptosis was determined in vitro and in vivo. Platinum level in A549 cells and tumor tissue was measured by atomic absorption spectrometry (AAS). The binding ability of specificity protein 1 (Sp1) to CTR1 and Sp1 promoters was detected by ChIP assay and luciferase reporter assay system.
    RESULTS: Here we show that combined curcumin and cisplatin treatment markedly inhibited A549 cells proliferation and induced its apoptosis. Using a mouse model of A549 xenograft, we demonstrated that curcumin inhibits copper influx and increases uptake of platinum ion in tumor. Curcumin treatment enhances the binding of Sp1 to CTR1 and Sp1 promoters, thus induces CTR1 expression and chemosensitization to cisplatin treatment. This process is regulated by the Cu-Sp1-CTR1 regulatory loop. Moreover, the enhancement mediated by curcumin on cisplatin therapeutic efficacy in cultured human NSCLC cell lines (A549, H460, H1299) was dependent on CTR1.
    CONCLUSIONS: Our results demonstrated copper chelator curcumin enhances the benefits of platinum-containing chemotherapeutic agents and CTR1 could be a promising therapeutic target for non-small cell lung cancer treatment.
    Keywords:  CTR1; Cisplatin sensitivity; Copper chelation; Curcumin; Sp1
  2. J Biomed Inform. 2018 Sep 06. pii: S1532-0464(18)30178-3. [Epub ahead of print]
    Selvaraj G, Kaliamurthi S, Chandra Kaushik A, Khan A, Wei YK, Cho WC, Gu K, Wei DQ.
      BACKGROUND: Lung adenocarcinoma (LUAD) is a heterogeneous disease with poor survival in the advanced stage and a high incidence rate in the world. Novel drug targets are urgently required to improve patient treatment. Therefore, we aimed to identify therapeutic targets for LUAD based on protein-protein and protein-drug interaction network analysis with neural network algorithms using mRNA expression profiles.RESULTS: A comprehensive meta-analysis of selective non-small cell lung cancer (NSCLC) mRNA expression profile datasets from Gene Expression Omnibus were used to identify potential biomarkers and the molecular mechanisms related to the prognosis of NSCLC patients. Using the Network Analyst tool, based on combined effect size (ES) methods, we recognized 6,566 differentially expressed genes (DEGs), which included 3,036 downregulated and 3,530 upregulated genes linked to NSCLC patient survival. ClueGO, a Cytoscape plugin, was exploited to complete the function and pathway enrichment analysis, which disclosed "regulated exocytosis", "purine nucleotide binding", "pathways in cancer", and "cell cycle" between exceptionally supplemented terms. Enrichr, a web tool examination, demonstrated "early growth response protein 1 (EGR-1)", "hepatocyte nuclear factor 4α (HNF4A)", "mitogen-activated protein kinase 14 (MAP3K14)", and "cyclin-dependent kinase 1 (CDK1)" to be among the most prevalent TFs and kinases associated with NSCLC. Our meta-analysis identified that MAPK1 and aurora kinase (AURKA) are the most obvious class of hub nodes. Furthermore, protein-drug interaction network and neural network algorithms identified candidate drugs such as phosphothreonine and 4-(4-methylpiperazin-1-yl)-n-[5-(2-thienylacetyl)-1,5-dihydropyrrolo[3,4-c]pyrazol-3-yl] benzamide and for the targets MAPK1 and AURKA, respectively.
    CONCLUSION: Our study has identified novel candidate biomarkers, pathways, transcription factors (TFs), and kinases associated with NSCLC prognosis, as well as drug candidates, which may assist treatment strategy for NSCLC patients.
    Keywords:  Network Analyst; STRING; Walktrap module; hub nodes; lung adenocarcinoma; microarray data; neural network
  3. J Photochem Photobiol B. 2018 Aug 23. pii: S1011-1344(18)30517-7. [Epub ahead of print]188 28-41
    P V, D D, Bala M, N S.
      Carbon monoxide releasing molecules (CORMs) are organometallic/organic compounds that release carbon monoxide (CO) spontaneously or upon activation. PhotoCORMs are capable of releasing CO on light based activation. This group of molecules is used in photodynamic therapy due to their ability to release CO in a controlled manner. In the present investigation, the release of CO from [Mn(CO)3Br(μ-bpcpd)]2 (MnCORM) upon irradiation at λmax 365 nm was assessed spectrophotometrically using myoglobin assay and confirmed by liquid FT-IR spectroscopic analysis. Further, the cytotoxic potential of MnCORM on normal cells (HEK 293) and cancer cell lines such as lung (A549), cervical (HeLa), breast (MDA MB-231) and colon (HCT-15) was evaluated. The IC50 values of MnCORM were found to be 21.37 ± 1.72, 24.12 ± 1.03, 21.89 ± 0.59 and 13.69 ± 0.91 μM on cervical (HeLa), lung (A549), colon (HCT-15) and breast (MDA MB-231) cancer cells respectively. An inquest into the nature of cell death was confirmed based on the nuclear and cytological examinations, flow cytometric analyses and protein expression studies. The AO/EB dual staining and cytological evaluation of the treated cells revealed that the cell death might be due to apoptosis. The flow cytometric analysis of propidium iodide (PI) stained cells showed a significant amount of sub-G1 hypodiploid cells due to MnCORM treatment. The MnCORM-induced apoptosis was mediated through the generation of reactive oxygen species (ROS), specifically superoxide radicals leading to loss of mitochondrial membrane potential. The intrinsic pathway of apoptosis was elucidated based on the expression studies of pro-apoptotic and apoptotic proteins such as bcl-2, bax, cyt c, cleaved caspase-3, cleaved caspase-9 and cleaved PARP. Due to its innate potential to release CO upon photoactivation and its ability to induce apoptosis via intrinsic pathway, the MnCORM molecule could be exploited for controlled release and photodynamic cancer therapy.
    Keywords:  Apoptosis; Carbon Monoxide Releasing Molecule; Photoactivation; Targeted Therapy
  4. Toxicol Appl Pharmacol. 2018 Sep 06. pii: S0041-008X(18)30404-6. [Epub ahead of print]
    Zhu J, Wang H, Chen F, Lv H, Xu Z, Fu J, Hou Y, Xu Y, Pi J.
      Non-small cell lung cancer (NSCLC) has a high mortality rate worldwide. Various treatments strategies have been used against NSCLC including individualized chemotherapies, but innate or acquired cancer cell drug resistance remains a major obstacle. Recent studies revealed that the Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway is intimately involved in cancer progression and chemoresistance. Thus, antagonizing Nrf2 would seem to be a viable strategy in cancer therapy. In the present study a traditional Chinese medicine, triptolide, was identified that markedly inhibited expression and transcriptional activity of Nrf2 in various cancer cells, including NSCLC and liver cancer cells. Consequently, triptolide made cancer cells more chemosensitivity toward antitumor drugs both in vitro and in a xenograft tumor model system using lung carcinoma cells. These results suggest that triptolide blocks chemoresistance in cancer cells by targeting the Nrf2 pathway. Triptolide should be further investigated in clinical cancer trials.
    Keywords:  Chemoresistance; NSCLC; Nrf2; Triptolide
  5. Redox Biol. 2018 Aug 22. pii: S2213-2317(18)30528-7. [Epub ahead of print]19 235-249
    Levings DC, Wang X, Kohlhase D, Bell DA, Slattery M.
      NRF2 is a redox-responsive transcription factor that regulates expression of cytoprotective genes via its interaction with DNA sequences known as antioxidant response elements (AREs). NRF2 activity is induced by oxidative stress, but oxidative stress is not the only context in which NRF2 can be activated. Mutations that disrupt the interaction between NRF2 and KEAP1, an inhibitor of NRF2, lead to NRF2 hyperactivation and promote oncogenesis. The mechanisms underlying NRF2's oncogenic properties remain unclear, but likely involve aberrant expression of select NRF2 target genes. We tested this possibility using an integrative genomics approach to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations. This approach revealed a core set of 32 direct NRF2 targets that are consistently upregulated in NRF2 hyperactivated tumors. This set of NRF2 "cancer target genes" includes canonical redox-related NRF2 targets, as well as target genes that have not been previously linked to NRF2 activation. Importantly, NRF2-driven upregulation of this gene set is largely independent of the organ system where the tumor developed. One key distinguishing feature of these NRF2 cancer target genes is that they are regulated by high affinity AREs that fall within genomic regions possessing a ubiquitously permissive chromatin signature. This implies that these NRF2 cancer target genes are responsive to oncogenic NRF2 in most tissues because they lack the regulatory constraints that restrict expression of most other NRF2 target genes. This NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity, and high NRF2 activity is associated with significant decreases in survival in multiple cancer types. Overall, the pervasive upregulation of these NRF2 cancer targets across multiple cancers, and their association with negative outcomes, suggests that these will be central to dissecting the functional implications of NRF2 hyperactivation in several cancer contexts.