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Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9.

ABSTRACT: We cloned a new inhibitor of apoptosis protein (IAP) homolog, SfIAP, from Spodoptera frugiperda Sf-21 cells, a host of insect baculoviruses. SfIAP contains two baculovirus IAP repeat domains followed by a RING domain. SfIAP has striking amino acid sequence similarity with baculoviral IAPs, CpIAP and OpIAP, suggesting that baculoviral IAPs may be host-derived genes. SfIAP and baculoviral CpIAP inhibit Bax but not Fas-induced apoptosis in human cells. Their apoptosis-suppressing activity in mammalian cells requires both baculovirus IAP repeat and RING domains. Further biochemical data suggest that SfIAP and CpIAP are specific inhibitors of mammalian caspase-9, the pinnacle caspase in the mitochondria/cytochrome c pathway for apoptosis, but are not inhibitors of downstream caspase-3 and caspase-7. Thus the mechanisms by which insect and baculoviral IAPs suppress apoptosis may involve inhibition of an insect caspase-9 homologue. Peptides representing the IAP-binding domain of the Drosophila cell death protein Grim abrogated human caspase suppression by SfIAP and CpIAP, implying evolutionary conservation of the functions of IAPs and their inhibitors.

SUBMITTER: Huang Q

PROVIDER: S-EPMC26450 | biostudies-literature | 2000 Feb

REPOSITORIES: biostudies-literature

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Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9.

Huang Q Q Deveraux Q L QL Maeda S S Salvesen G S GS Stennicke H R HR Hammock B D BD Reed J C JC

Proceedings of the National Academy of Sciences of the United States of America 20000201 4

We cloned a new inhibitor of apoptosis protein (IAP) homolog, SfIAP, from Spodoptera frugiperda Sf-21 cells, a host of insect baculoviruses. SfIAP contains two baculovirus IAP repeat domains followed by a RING domain. SfIAP has striking amino acid sequence similarity with baculoviral IAPs, CpIAP and OpIAP, suggesting that baculoviral IAPs may be host-derived genes. SfIAP and baculoviral CpIAP inhibit Bax but not Fas-induced apoptosis in human cells. Their apoptosis-suppressing activity in mammal ...[more]

PMID: 10677478

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Project description:BackgroundHepatocellular carcinoma (HCC), often diagnosed at advanced stages without curative therapies, is the fifth most common malignant cancer and the second leading cause of cancer-related mortality. Polo-like kinase 1 (PLK1) is activated in the late G2 phase of the cell cycle and is required for entry to mitosis. Interestingly, PLK1 is overexpressed in many HCC patients and is highly associated with poor clinical outcome. Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is also highly overexpressed in HCC and plays key roles in this malignancy.AimTo determine the expression patterns of PLK1 and BIRC5, as well as their correlation with p53 mutation status and patient clinical outcome.MethodsThe expression patterns of PLK1 and BIRC5, and their correlation with p53 mutation status or patient clinical outcome were analyzed using a TCGA HCC dataset. Cell viability, cell apoptosis, and cell cycle arrest assays were conducted to investigate the efficacy of the PLK1 inhibitors volasertib and GSK461364 and the BIRC5 inhibitor YM155, alone or in combination. The in vivo efficacy of volasertib and YM155, alone or in combination, was assessed in p53-mutated Huh7-derived xenograft models in immune-deficient NSIG mice.ResultsOur bioinformatics analysis using a TCGA HCC dataset revealed that PLK1 and BIRC5 were overexpressed in the same patient subset and their expression was highly correlated. The overexpression of both PLK1 and BIRC5 was more frequently detected in HCC with p53 mutations. High PLK1 or BIRC5 expression significantly correlated with poor clinical outcome. PLK1 inhibitors (volasertib and GSK461364) or a BIRC5 inhibitor (YM155) selectively targeted Huh7 cells with mutated p53, but not HepG2 cells with wild-type p53. The combination treatment of volasertib and YM155 synergistically inhibited the viability of Huh7 cells via apoptotic pathway. The efficacy of volasertib and YM155, alone or in combination, was validated in vivo in a Huh7-derived xenograft model.ConclusionPLK1 and BIRC5 are highly co-expressed in p53-mutated HCC and inhibition of both PLK1 and BIRC5 synergistically compromises the viability of p53-mutated HCC cells in vitro and in vivo.

Dataset Information

Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9.

Publications

Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9.

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