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  • br Discussion and conclusions br Cancer cells can reprogram

    2020-08-18


    4. Discussion and conclusions
    Cancer Anisomycin can reprogram metabolism to support their prolifera-tion and growth. The PHGDH gene involved in cancer metabolic re-programming is located at chromosome 1p12, which shows copy-number gain in 16% of all cancers including 40% of melanoma and some triple-negative breast cancers [19]. Currently, the discovery of drugs targeting at PHGDH is mainly concentrated on breast cancer, more studies on other tumor types remain to be carried out.
    Three studies have reported some compounds with anti-PHGDH activity recently. The first PHGDH inhibitor CBR-5884 was found by screening 800,000-compound library and showed enzymatic inhibitory activity with an IC50 of 33.0 ± 12.0 μM in a time-dependent manner. It was speculated that CBR-5884 was a noncompetitive inhibitor and disrupted the oligomerization state of PHGDH. Serine metabolism was detected by gas chromatography-mass spectrometry, and CBR-5884 specifically inhibited 30% of de novo serine synthesis. Furthermore, CBR-5884 had been shown to inhibit cell proliferation in PHGDH-overexpressing cancer cell lines. However, the binding of CBR-5884 with PHGDH and its targeting to PHGDH remain to be studied [5]. Another reported non-competitive inhibitor NCT-503 exhibited the best IC50 value of 2.5 ± 0.6 μM by screening 400,000-compound of NIH molecular libraries and showed some selectivity in PHGDH-amplified breast cancer cell lines. Although NCT-503 was found to be non-com-petitive, its specific binding site remains unknown [3]. The third study reported two allosteric inhibitors for PHGDH using a structure-based design approach with an optimal IC50 of 28.1 ± 1.3 μM. And it was confirmed that PKUMDL-WQ-2101 and PKUMDL-WQ-2201 specifically bind to PHGDH in PHGDH-amplified breast cancer cells [13].
    In our research, azacoccone E was found by screening in-house database of NPs and found to have an optimal IC50 of 9.8 ± 4.3 μM. The enzyme activity kinetics study confirmed that the azacoccone E was a non-competitive inhibitor in a time-dependent manner. The further MST method and the cell level CETSA assay were performed to verify that azacoccone E directly bound to PHGDH. Meanwhile, azacoccone E selectively inhibited PHGDH-amplified cancer cell proliferation and showed a dose-dependent proapoptotic activity in Hela cells. Molecular docking demonstrated that azacoccone E coordinated at the allosteric site of PHGDH, which is essential for the ability of diminishing the enzyme activity. Moreover, azacoccone E is the first PHGDH inhibitor derived from natural products and provides a new scaffold for the study  Bioorganic Chemistry 87 (2019) 16–22
    of anti-tumor drug research targeting PHGDH. In our future research, more detailed anti-tumor mechanisms of azacoccone E will be studied, and more pre-clinical evaluations will be performed.
    Acknowledgements
    Competing interests
    The authors have declared that no competing interest exists.
    Appendix A. Supplementary material
    References
    22 Article
    BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
    Graphical Abstract Authors
    Clotilde Wiel, Kristell Le Gal,
    Volkan I. Sayin, Martin O. Bergo
    Correspondence
    In Brief
    Antioxidants stimulate lung cancer
    metastasis by reducing free heme levels
    and stabilizing the transcription
    factor BACH1
    Highlights
    d Antioxidants stimulate KRAS-driven lung cancer metastasis
    d Antioxidants reduce free heme levels and stabilize BACH1
    d BACH1 activates Hk2 and Gapdh transcription triggering glycolysis-induced metastasis
    d Targeting BACH1 or its glycolytic targets prevents antioxidant-induced metastasis
    Article
    BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
    Clotilde Wiel,1,2 Kristell Le Gal,3,4,7 Mohamed X. Ibrahim,2,7 Chowdhury Arif Jahangir,1 Muhammad Kashif,1 Haidong Yao,1 Dorian V. Ziegler,2 Xiufeng Xu,1 Tanushree Ghosh,5 Tanmoy Mondal,5 Chandrasekhar Kanduri,5 Per Lindahl,6 Volkan I. Sayin,3,4,* and Martin O. Bergo1,2,8,* 1Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden
    2Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden
    3Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden 4Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden
    5Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden 6The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden