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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.
Sec. Cell Death and Survival
Volume 12 - 2024 | doi: 10.3389/fcell.2024.1471216

Targeting caspase-8/c-FLIPL heterodimer in complex II promotes DL-mediated cell death

Provisionally accepted
Laura Hillert-Richter Laura Hillert-Richter Corinna Koenig Corinna Koenig Nikita Ivanisenko Nikita Ivanisenko Dirk Reinhold Dirk Reinhold Inna N. Lavrik Inna N. Lavrik *
  • Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany

The final, formatted version of the article will be published soon.

    Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIPL heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIPL heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks.

    Keywords: Cell Death, complex II, c-FLIP, FLIPin, caspase-8, SMAC mimetic, CD95

    Received: 26 Jul 2024; Accepted: 13 Sep 2024.

    Copyright: © 2024 Hillert-Richter, Koenig, Ivanisenko, Reinhold and Lavrik. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Inna N. Lavrik, Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany

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