Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse
Aladin Haimovici,Christoph Höfer,Mohamed Tarek Badr,Elham Bavafaye Haghighi,Tarek Amer,Melanie Boerries,Peter Bronsert,Ievgen Glavynskyi,Deborah Fanfone,Gabriel Ichim,Nico Thilmany,Arnim Weber,Tilman Brummer,Corinna Spohr,Rupert Öllinger,Klaus-Peter Janssen,Roland Rad,Georg Häcker +17 more
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In this article , the authors tested whether spontaneously appearing micronuclei in cancer cells are linked to sub-lethal apoptotic signals and found that low-level activity in the mitochondrial apoptosis apparatus operates through CAD-dependent gene induction and STING-activation and has substantial impact on metastasis in cancer patients.Abstract:
Micronuclei are DNA-containing structures separate from the nucleus found in cancer cells. Micronuclei are recognized by the immune sensor axis cGAS/STING, driving cancer metastasis. The mitochondrial apoptosis apparatus can be experimentally triggered to a non-apoptotic level, and this can drive the appearance of micronuclei through the Caspase-activated DNAse (CAD). We tested whether spontaneously appearing micronuclei in cancer cells are linked to sub-lethal apoptotic signals. Inhibition of mitochondrial apoptosis or of CAD reduced the number of micronuclei in tumor cell lines as well as the number of chromosomal misalignments in tumor cells and intestinal organoids. Blockade of mitochondrial apoptosis or deletion of CAD reduced, while experimental activation CAD, STING-dependently, enhanced aggressive growth of tumor cells in vitro. Deletion of CAD from human cancer cells reduced metastasis in xenograft models. CAD-deficient cells displayed a substantially altered gene-expression profile, and a CAD-associated gene expression 'signature' strongly predicted survival in cancer patients. Thus, low-level activity in the mitochondrial apoptosis apparatus operates through CAD-dependent gene-induction and STING-activation and has substantial impact on metastasis in cancer. read more
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Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis
TL;DR: Eskandari and Eaves review evidence of caspase-3-regulated protein quality, proliferation, differentiation, and tumorigenic activity in viable cells.
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Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?
Georg Häcker,Aladin Haimovici +1 more
TL;DR: In this article , the authors suggest that small-scale mitochondrial outer membrane permeabilization is an accident, a leakiness of the apoptosis apparatus, perhaps during restructuring of the mitochondrial network.
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Pattern Recognition Receptors of Nucleic Acids Can Cause Sublethal Activation of the Mitochondrial Apoptosis Pathway during Viral Infection
TL;DR: This work suggests the alternative interpretation that PRRs do not have the primary function to induce apoptosis but to trigger sublethal signals in the apoptosis system, and test this hypothesis during infection of epithelial cells with modified vaccinia virus Ankara (MVA).
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Micronuclei in Circulating Tumor Associated Macrophages Predicts Progression in Advanced Colorectal Cancer
Dimpal M. Kasabwala,Raymond C. Bergan,K. Gardner,Rena G. Lapidus,Susan Tsai,Mohammed Aldakkak,Daniel L. Adams +6 more
TL;DR: Micronuclei (MN) are fragments of damaged nucleic acids which budded from a cell's nuclei as a repair mechanism for chromosomal instabilities, which within circulating white blood cells (cWBCs) signifies increased cancer risk, and in tumor cells indicates aggressive subtypes as discussed by the authors .
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