Manipulation of NK cytotoxicity by the IAP family member Livin

Nachmias, Boaz; Mizrahi, Sa’ar; Elmalech, Meital; Lazar, Itay; Ashhab, Yaqoub; Gazit, Roi; Markel, Gal; Ben‐Yehuda, Dina; Mandelboim, Ofer

doi:10.1002/eji.200636600

Cited by 17 publications

(14 citation statements)

References 52 publications

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“…We previously showed that noncleavable Livin protects cells from human NK cell-induced cytotoxicity (6). Here, we show in vivo using NK-deficient mice (Fig.…”

Section: Discussionsupporting

confidence: 62%

“…We generated retroviral constructs by subcloning the Livin cDNA into the pWZL IRES-blasticidin (subcloned into EcoRI-BglII sites) and pBabe-neomycin (subcloned into EcoRI-Sal1 sites) vector systems. Livin mutants were described previously (4,6,7). We created amphotropic retroviruses by transient cotransfection of 10-cm plates of 293T cells with 3 Ag of appropriate packaging plasmid pCL-10A1 for Moloney-based virus infections and CMV R8.91, CMV-VSV-G for lentiviral infections (P lentilox 3.7), and 5 Ag of carrier vector using FuGene 6 (Roche).…”

Section: Methodsmentioning

confidence: 99%

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The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity

Abd‐Elrahman¹,

Hershko

Neuman

et al. 2009

Cancer Research

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The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We and others previously described the IAP Livin (ML-IAP). We found that Livin is unique among the IAP members as, on a strong apoptotic stimulus, it is specifically cleaved by caspases to produce a truncated protein with paradoxical proapoptotic activity (tLivin). We also showed that Livin encodes two splicing variants, termed Livin A and B, with diverse antiapoptotic effects in vitro. In this study, we compared the Livin isoforms in vivo. An animal model was established and the effects of Livin A and B on the initiation and development of tumors were compared. In the animal model, Livin A promotes tumor initiation in comparison with control. Interestingly, the growth of tumors originating from cells expressing Livin B was inhibited. In these tumors, Livin B was cleaved and produced a high level of the proapoptotic tLivin B that repressed tumor development. When we eliminated the proapoptotic effect of Livin B by point mutations, the resulting antiapoptotic Livin B mutants contributed to tumor progression. In terms of mechanism, we show that Livin B tumors develop only in mice lacking natural killer (NK) cell activity. Thus, from the animal model, we can conclude that Livin plays a major role in tumorigenicity and that NK cells induce cleavage of Livin to its proapoptotic truncated protein that in turn inhibits tumor growth. Therefore, Livin and tLivin may serve as potential targets for cancer therapy. [Cancer Res 2009;69(13):5475-80]

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“…We previously showed that noncleavable Livin protects cells from human NK cell-induced cytotoxicity (6). Here, we show in vivo using NK-deficient mice (Fig.…”

Section: Discussionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity

Abd‐Elrahman¹,

Hershko

Neuman

et al. 2009

Cancer Research

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“…apoptosis of Jurkat cells (21). Therefore, it is perplexing to illustrate the diverse roles Livin isoforms play, but isoformspecific therapy might offer an alternative opportunity to target tumors in the near future.…”

Section: Livin Biologymentioning

confidence: 99%

Challenge and promise: roles for Livin in progression and therapy of cancer

Wang

Zhang²,

Liu

et al. 2008

Molecular Cancer Therapeutics

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Livin is a member of the inhibitors of apoptosis protein gene family, which is highly expressed in a variety of human neoplasms. Several studies have shown that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential, and sensitizes tumor cells to chemotherapeutic drugs. Furthermore, emerging data reveal that Livin fragments cleavaged by caspases restored paradoxical proapoptotic activity during the apoptotic process, suggesting that Livin cleavage will become a highly potent proapoptotic agent in the future. In this article, we review the current understanding of the versatile roles of Livin in the apoptotic cascade and exploit the promising approach to interfere with Livin as a novel strategy for cancer therapy. [Mol Cancer Ther 2008;7(12):3661 -9]

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“…We previously found that Livin is specifically cleaved by caspases at the Asp52 residue to produce a large C-terminal fragment, containing both the BIR and the RING domains. After cleavage, truncated Livin (tLivin) acts paradoxically as a proapoptotic factor (18,19).In the present study we show that chemoresistant melanoma primary cultures that highly express the Livin protein are sen-* Corresponding author. Mailing address:…”

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confidence: 92%

mentioning

confidence: 99%

The Oncolytic Activity of Newcastle Disease Virus NDV-HUJ on Chemoresistant Primary Melanoma Cells Is Dependent on the Proapoptotic Activity of the Inhibitor of Apoptosis Protein Livin

Lazar

Barak

Shiloach

et al. 2010

J Virol

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Patients with advanced melanoma usually do not benefit from conventional chemotherapy treatment. There is therefore a true need for a new kind of therapy for melanoma. One factor responsible for the poor prognosis of melanoma is the inhibitor of apoptosis protein (IAP) family member Livin. In this study, we applied a novel approach for the treatment of melanoma, using a unique strain of the oncolytic Newcastle disease virus (NDV-HUJ). We found that, unlike chemotherapeutic drugs, NDV-HUJ, a one-cycle replicating virus, overcomes the resistance to apoptosis of melanoma primary cultures that over express the Livin protein. Newcastle disease virus (NDV) is an avian paramyxovirus that has a potential selective oncolytic effect on human tumors (5,7,13,21,25, 26). NDV's natural host is avian, and while mammalian cells bear the sialic acid receptor for NDV and may be infected by the virus, the virus has limited replication capacity in normal mammalian cells (21). We recently reported the development of an attenuated (lentogenic) isolate of NDV (HUJ) that undergoes only one cycle replication in infected mammalian cells (7,25). NDV-HUJ is a single clone derived from the parental strain NDV Hitchner B1, which contains a mixed viral population. The new virus clone is attenuated due to multiple passages in specific-pathogen-free (SPF) eggs, and its intracerebral pathogenicity index (ICPI) value is low (an ICPI of 0.01 versus an ICPI of 0.93 for the parental NDV Hitchner B1). Sequence analysis of NDV-HUJ indicated 156 changes at the nucleotide sequence level and multiple amino acid changes from the parental B1 virus in all six viral genes (see Fig. S1 in the supplemental material). Although NDV-HUJ is an attenuated virus in chicken, it retains a selective cytotoxic potential for cancer cells, as determined in vitro and in vivo, using murine and human lung carcinomas (25). The oncolytic effect of the virus is apoptosis dependent (25).NDV-HUJ has been applied to treat glioblastoma patients in a phase I/II clinical trials and found to be safe and potentially active (7).The inhibitors of apoptosis proteins (IAPs) are receiving increased attention as key players in the initiation of tumors, their progression, and resistance to chemotherapy treatment (17). To date, eight human IAPs have been identified, including Livin. IAPs are characterized by one or more repeats of a highly conserved 70-amino-acid domain termed the baculovirus IAP repeat (BIR) that can bind and inhibit caspases, some IAPs also contain a conserved sequence termed the RING finger. RING finger proteins might function as E3 ubiquitin ligases; however, the exact nature of the E3 ligase activity of IAPs is still largely unclear.IAPs inhibit apoptosis induced by a variety of stimuli, mainly through their ability to bind and inhibit specific caspases (17). Intense study has shown that the role of IAP in apoptosis regulation is highly diverse, with a prominent role in tumorigenesis and resistance to therapy. Among the human IAPs, XIAP is the best characterized and the m...

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Manipulation of NK cytotoxicity by the IAP family member Livin

Cited by 17 publications

References 52 publications

The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity

The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity

Challenge and promise: roles for Livin in progression and therapy of cancer

The Oncolytic Activity of Newcastle Disease Virus NDV-HUJ on Chemoresistant Primary Melanoma Cells Is Dependent on the Proapoptotic Activity of the Inhibitor of Apoptosis Protein Livin

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