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      Apoptosis regulation in adrenocortical carcinoma

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          Abstract

          Apoptosis evading is a hallmark of cancer. Tumor cells are characterized by having an impaired apoptosis signaling, a fact that deregulates the balance between cell death and survival, leading to tumor development, invasion and resistance to treatment. In general, patients with adrenocortical carcinomas (ACC) have an extremely bad prognosis, which is related to disease progression and significant resistance to treatments. In this report, we performed an integrative review about the disruption of apoptosis in ACC that may underlie the characteristic poor prognosis in these patients. Although the apoptosis has been scarcely studied in ACC, the majority of the deregulation phenomena already described are anti-apoptotic. Most importantly, in a near future, targeting apoptosis modulation in ACC patients may become a promising therapeutic.

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          Most cited references132

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          Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.

          We report here that BID, a BH3 domain-containing proapoptotic Bcl2 family member, is a specific proximal substrate of Casp8 in the Fas apoptotic signaling pathway. While full-length BID is localized in cytosol, truncated BID (tBID) translocates to mitochondria and thus transduces apoptotic signals from cytoplasmic membrane to mitochondria. tBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c independent of caspase activity, and then the loss of mitochondrial membrane potential, cell shrinkage, and nuclear condensation in a caspase-dependent fashion. Coexpression of BclxL inhibits all the apoptotic changes induced by tBID. Our results indicate that BID is a mediator of mitochondrial damage induced by Casp8.
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            Molecular characterization of mitochondrial apoptosis-inducing factor.

            Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.
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              Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.

              Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                May 2019
                11 April 2019
                : 8
                : 5
                : R91-R104
                Affiliations
                [1 ]Instituto de Investigação e Inovação em Saúde (I3S) , Universidade do Porto, Porto, Portugal
                [2 ]Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) , Porto, Portugal
                [3 ]Endocrine , Cardiovascular & Metabolic Research, Department of Anatomy, Multidisciplinary Unit for Biomedical Research (UMIB), Instituto de Ciências Biomédicas Abel Salazar, University of Porto (ICBAS/UP), Porto, Portugal
                [4 ]Department of Pediatrics , Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
                [5 ]Department of Endocrinology , Hospital S. João, Porto, Portugal
                Author notes
                Correspondence should be addressed to D Pignatelli: dpignatelli@ 123456ipatimup.pt
                Article
                EC-19-0114
                10.1530/EC-19-0114
                6510712
                30978697
                881b806e-bb15-4a6e-995d-70f50daaaee5
                © 2019 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 03 April 2019
                : 11 April 2019
                Categories
                Review

                adrenocortical tumors,adrenocortical carcinomas,apoptosis,molecular deregulations

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