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Caspase-10: a molecular switch from cell-autonomous apoptosis to communal cell death in response to chemotherapeutic drug treatment.

Mohr, Andrea and Deedigan, Laura and Jencz, Sylwia and Mehrabadi, Yasamin and Houlden, Lily and Albarenque, Stella-Maris and Zwacka, Ralf M (2018) 'Caspase-10: a molecular switch from cell-autonomous apoptosis to communal cell death in response to chemotherapeutic drug treatment.' Cell Death and Differentiation, 25 (2). pp. 340-352. ISSN 1350-9047

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The mechanisms of how chemotherapeutic drugs lead to cell cycle checkpoint regulation and DNA damage repair are well understood, but how such signals are transmitted to the cellular apoptosis machinery is less clear. We identified a novel apoptosis-inducing complex, we termed FADDosome, which is driven by ATR-dependent caspase-10 upregulation. During FADDosome-induced apoptosis, cFLIPL is ubiquitinated by TRAF2, leading to its degradation and subsequent FADD-dependent caspase-8 activation. Cancer cells lacking caspase-10, TRAF2 or ATR switch from this cell-autonomous suicide to a more effective, autocrine/paracrine mode of apoptosis initiated by a different complex, the FLIPosome. It leads to processing of cFLIPL to cFLIPp43, TNF-α production and consequently, contrary to the FADDosome, p53-independent apoptosis. Thus, targeting the molecular levers that switch between these mechanisms can increase efficacy of treatment and overcome resistance in cancer cells.Cell Death and Differentiation advance online publication, 3 November 2017; doi:10.1038/cdd.2017.164.

Item Type: Article
Uncontrolled Keywords: HCT116 Cells; HT29 Cells; Animals; Humans; Mice; Mice, Nude; Fluorouracil; Antineoplastic Combined Chemotherapy Protocols; Ligands; Apoptosis; Cell Proliferation; Female; Caspase 10; Membrane Potential, Mitochondrial
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 28 Nov 2017 09:45
Last Modified: 18 Aug 2022 11:40

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