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Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks

  • Author Footnotes
    6 These authors contributed equally to this work
    Nikita V. Ivanisenko
    6 These authors contributed equally to this work
    The Federal Research Center Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia

    Artificial Intelligence Research Institute, Moscow, Russia
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  • Author Footnotes
    6 These authors contributed equally to this work
    Kamil Seyrek
    6 These authors contributed equally to this work
    Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany
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  • Laura K. Hillert-Richter
    Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany
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  • Corinna König
    Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany
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  • Johannes Espe
    Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany
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  • Kakoli Bose
    Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India

    Homi Bhabha National Institute, BARC Training School Complex, Anushaktinagar, Mumbai 400094, India
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  • Inna N. Lavrik
    The Federal Research Center Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia

    Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany
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  • Author Footnotes
    6 These authors contributed equally to this work
Published:December 29, 2021DOI:


      • c-FLIP is a master regulator of death receptor-induced apoptosis.
      • The molecular architecture of the death-inducing signaling complex (DISC) is strongly regulated by c-FLIP proteins. Recently, several structural and mechanistic models of this control have been proposed.
      • c-FLIP can act in both a pro- and antiapoptotic manner in cancer cells.
      • c-FLIP is a promising target in cancer.
      • Targeting c-FLIP has a great potential to sensitize cancer cells towards apoptosis induction.
      The extrinsic pathway is mediated by death receptors (DRs), including CD95 (APO-1/Fas) or TRAILR-1/2. Defects in apoptosis regulation lead to cancer and other malignancies. The master regulator of the DR networks is the cellular FLICE inhibitory protein (c-FLIP). In addition to its key role in apoptosis, c-FLIP may exert other cellular functions, including control of necroptosis, pyroptosis, nuclear factor κB (NF-κB) activation, and tumorigenesis. To gain further insight into the molecular mechanisms of c-FLIP action in cancer networks, we focus on the structure, isoforms, interactions, and post-translational modifications of c-FLIP. We also discuss various avenues to target c-FLIP in cancer cells for therapeutic benefit.


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