Nachmias B, Ashhab Y, Ben Yehuda DThe inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 14:231-243
Department of Hematology, Hadassah University Hospital, Ein-Karem, P.O.B. 12000, Jerusalem 91120, Israel. Seminars in Cancer Biology
(Impact Factor: 9.33).
09/2004; 14(4):231-43. DOI: 10.1016/j.semcancer.2004.04.002
Apoptosis is a crucial biological process that prevents uncontrolled cell proliferation and eliminates harmful cells. Resistance to apoptotic stimuli is a hallmark feature of various cancers. One of the mechanisms through which tumor cells are believed to acquire resistance to apoptosis is by overexpression of inhibitor of apoptosis proteins (IAPs). IAPs are a group of structurally related proteins that were initially identified in baculoviruses. Mammalian IAPs block apoptosis either by binding and inhibiting caspases or through caspase-independent mechanisms. This family of proteins has become increasingly prominent in the field of cancer biology. To date, overexpression of several IAPs has been detected in various cancers. This paper reviews the recent advances in the research of IAPs. The differential expression and the biological significance of each IAP in various cancer types will be discussed. Finally, we review the most recent advances in the research efforts aimed at using IAPs as potential targets for cancer therapy.
Available from: PubMed Central
- "Several IAP proteins have been shown to regulate apoptosis in a Caspase-independent manner through the JNK or NF-κB signaling pathways (38–40). Interestingly, IAPs function as E3 ubiquitin ligases and can target cellular proteins for proteasomal degradation, this process being essential for apoptosis (41). IAPs activities are regulated by second mitochondria derived activator of Caspases (smac) (42). "
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ABSTRACT: Autoimmune diseases are characterized by the production of antibodies against self-antigens and generally arise from a failure of central or peripheral tolerance. However, these diseases may develop when newly appearing antigens are not recognized as self by the immune system. The mechanism by which some antigens are "invisible" to the immune system is not completely understood. Apoptotic and complement system defects or autophagy imbalance can generate this antigenic autoreactivity. Under particular circumstances, cellular debris containing autoreactive antigens can be recognized by innate immune receptors or other sensors and can eventually lead to autoimmunity. Ubiquitination may be one of the mechanisms protecting autoreactive antigens from the immune system that, if disrupted, can lead to autoimmunity. Ubiquitination is an essential post-translational modification used by cells to target proteins for degradation or to regulate other intracellular processes. The level of ubiquitination is regulated during T cell tolerance and apoptosis and E3 ligases have emerged as a crucial signaling pathway for the regulation of T cell tolerance toward self-antigens. I propose here that an unrecognized role of ubiquitin and ubiquitin-like proteins could be to render intracellular or foreign antigens (present in cellular debris resulting from apoptosis, complement system, or autophagy defects) invisible to the immune system in order to prevent the development of autoimmunity.
Available from: Ender Coskunpinar
- "A common polymorphism at the survivin gene promoter -31G/C has been shown to influence survivin expression and the risk for cancer. Studies carried out in tissue have suggested that survivin may have a critical role in the diagnosis, prognosis, and prediction of response to therapy (Altieri et al., 2003;Nachmias et al., 2004;Shinohara et al., 2005). The genetic variant -31G/C in the survivin promoter region has been associated with the overexpression of survivin at both the protein and the messenger RNA levels in cancer cells. "
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ABSTRACT: Lung cancer is the most common cancer worldwide. Survivin is one of the first reported inhibitors of apoptosis proteins, which is an important family of proteins that regulate apoptosis. The survivin gene is located on human chromosome 17q25, which is composed of 142 amino acids. A common polymorphism of the survivin gene promoter -31G/C has been shown to influence cancer risk. This genetic variant has been associated with overexpression of survivin at both protein and mRNA levels in cancer cells. We examined promoter (-31G\C) genotype frequency in a patient group (N = 146), 77.4% GG, 18.5% GC, 4.1% CC, and in a control group (N = 98), 57.1% GG, 34.7% GC, 8.2% CC. These distributions were significantly different. Promoter (-644C\T) genotype frequency in the patient group was 40.4% TT, 48.6% TC, 11% CC, and in the control group it was 551% TT, 40.8% TC, 4.1% CC; these distributions were also significantly different. Individuals carrying the survivin 31 GC genotype and those carrying the survivin 644 CC genotype had a significantly decreased risk of having non-small-cell lung cancer.
Available from: Elumalai Perumal
- "Defective apoptotic signaling pathways have an important role in the initiation and progression of cancer (Reed, 1999). One of the mechanisms through which tumor cells are believed to acquire resistance to apoptosis is overexpression of XIAP, which prevent apoptosis by specifically inhibiting caspases 3, 7, and 9 (Nachmias et al., 2004). Bcl-xL is an anti-apoptotic protein and a member of the Bcl-2 family, which includes Bcl-2, Bcl-w, Bcl-xs, and Mcl-1. "
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ABSTRACT: We aimed to investigate the cytotoxic effects of nimbolide, a limonoid present in leaves and flowers of the neem tree (Azadirachta indica) on human breast cancer cells. The molecular mechanisms involved in the apoptotic activity exerted by nimbolide were studied on the estrogen dependent (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cell lines. The growth inhibitory effect of nimbolide was assessed by MTT assay. Apoptosis induction by nimbolide treatment was determined by JC-1 mitochondrial membrane potential staining, cytochrome c release, caspase activation, cleavage of PARP and AO/EtBr dual staining. The modulation of apoptotic proteins (intrinsic pathway: Bax, bad, Bcl-2, Bcl-xL, Mcl-1, XIAP-1 and caspase-3, 9; extrinsic pathway: TRAIL, FasL, FADDR and Caspase-8) were studied by western blot and real time PCR analysis. Treatment with nimbolide resulted in dose and time-dependent inhibition of growth of MCF-7 and MDA-MB-231 cells. The occurrence of apoptosis in these cells was indicated by JC-1 staining, modulation of both intrinsic and extrinsic apoptotic signaling molecules expression and further apoptosis was confirmed by AO/EtBr dual staining. These events were associated with: increased levels of proapoptotic proteins Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c and reduced levels of the anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1 and XIAP-1. Nimbolide induces the cleavage of pro-caspase-8, pro-caspase-3 and PARP. The above data suggest that nimbolide induces apoptosis by both the intrinsic and extrinsic pathways. With evidence of above data it is suggested that nimbolide exhibit anticancer effect through its apoptosis-inducing property. Thus, nimbolide raises new hope for its use in anticancer therapy.
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