The serine protease Omi/HtrA2: a second mammalian protein with a Reaper-like function

Martins, L. Miguel

doi:10.1038/sj.cdd.4401044

Cited by 47 publications

(36 citation statements)

References 13 publications

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“…The functional significance of Smac/DIABLO release from the mitochondria was supported by the enhanced activation of caspase 3 and DNA fragmentation observed following the addition of the Smac-N7 peptide, when NF-B was inhibited, in the absence of TNF-␣. It is possible that other mitochondrial proteins such as Omi/HtrA2 may also have been involved (63). These observations are consistent with the interpretation that, in macrophages, XIAP was capable of suppressing caspase 9 activity or the activation of caspase 3 (12,61,62).…”

Section: Discussionsupporting

confidence: 81%

TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

Liu

Pagliari

et al. 2004

The Journal of Immunology

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Previously, we established that suppressing the constitutive activation of NF-κB in in vitro matured human macrophages resulted in apoptosis initiated by a decrease of the Bcl-2 family member, A1, and the loss of mitochondrial transmembrane potential (Δψm). This study was performed to characterize the mechanism of TNF-α-induced apoptosis in macrophages following the inhibition of NF-κB. The addition of TNF-α markedly enhanced the loss of Δψm and the induction of apoptotic cell death. Although caspase 8 was activated and contributed to DNA fragmentation, it was not necessary for the TNF-α-induced loss of Δψm. The inhibition of NF-κB alone resulted in the release of cytochrome c from the mitochondria, while both cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI were released following the addition of TNF-α. Furthermore, c-Jun N-terminal kinase activation, which was sustained following treatment with TNF-α when NF-κB was inhibited, contributed to DNA fragmentation. These observations demonstrate that cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI may be differentially released from the mitochondria, and that the sustained activation of c-Jun N-terminal kinase modulated the DNA fragmentation independent of the loss of Δψm.

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Section: Discussionsupporting

confidence: 81%

TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

Liu

Pagliari

et al. 2004

The Journal of Immunology

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“…Similarly to Smac/DIABLO, Omi/HtrA2 is a nuclearencoded protein possessing an NH 2 -terminal MLS that controls its import into the IMS (491,744). Omi/HtrA2 is proteolytically processed in the IMS from a 49-kDa precursor into a 37-kDa mature form, which presents an IBM at its NH 2 terminus (491,744).…”

Section: B Smac/diablo and Omi/htra2 Two Inhibitors Of Iapsmentioning

confidence: 99%

“…Omi/HtrA2 is proteolytically processed in the IMS from a 49-kDa precursor into a 37-kDa mature form, which presents an IBM at its NH 2 terminus (491,744). Omi/HtrA2 is a protease whose intramitochondrial targets have not been identified yet (665).…”

Section: B Smac/diablo and Omi/htra2 Two Inhibitors Of Iapsmentioning

confidence: 99%

Mitochondrial Membrane Permeabilization in Cell Death

Kroemer¹,

Galluzzi²,

Brenner³

2007

Physiological Reviews

3,179

2,742

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Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

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“…Marked overexpression of cleaved-caspase-3 and PARP was observed in 95-D/ A549 cells following nedaplatin and ABT-737 combination treatment. XIAP, plays a critical role in the regulation of apoptosis through inhibiting caspases (25). The present data suggested that the synergistic effect on apoptosis induced by nedaplatin plus ABT-737 was accompanied by a large reduction of XIAP.…”

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confidence: 49%

Nedaplatin enhanced apoptotic effects of ABT-737 in human cancer cells via Mcl-1 inhibition

Zhang

Weng

et al. 2016

Oncology Letters

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Abstract. Platinum compounds, such as cisplatin, carboplatin, oxaliplatin and nedaplatin, are widely used to treat a number of solid malignancies. Nedaplatin is a second-generation platinum complex, based on its pronounced anti-cancer activities against several solid tumors being equivalent to that of cisplatin, but with lower nephrotoxicity. In this context, the present study aimed to investigate the potential anti-cancer effect by combining nedaplatin with ABT-737. It was found that nedaplatin greatly increased ABT-737-mediated apoptosis in A549 and 95-D cells, accompanied by enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3. In addition, this enhancement was also paralleled by cytochrome c release and dissipation of mitochondrial membrane potential. Additional mechanistic investigations revealed that nedaplatin plus ABT-737 exerted a synergistic effect on cancer cells through their ability to accelerate the degradation of Mcl-1. The present study has revealed nedaplatin as a pertinent sensitizer to ABT-737, which opens up new avenues for this promising BH3-mimetic molecule in the clinic. IntroductionNedaplatin, a platinum derivative synthesized to overcome problems of cisplatin resistance, was developed by Shionogi Pharmaceutical Company in 1983 with the aim to provide a treatment with effectiveness similar to cisplatin, but with less nephrotoxicity and gastrointestinal toxicities (1). Nedaplatin produces promising response rates in clinical trials as a monotherapy for the treatment of squamous cell carcinoma of the uterus, cervix, head and neck, ovary, lung and esophagus (2-4). Nedaplatin exerts anti-tumor effects following uptake into tumor cells by binding to DNA bases and inhibiting DNA replication, similar to cisplatin and carboplatin (5). However, the ability of cancer cells to become resistant to nedaplatin remains a notable obstacle to successful chemotherapy; resistance of numerous species of cancer cells to nedaplatin can be reversed by combining with chemotherapeutic agents, including 5-fluorouracil, docetaxel and vindesine (6-8). The identification of new chemotherapy regimens incorporating nedaplatin with other chemotherapeutic agents can enhance the knowledge of nedaplatin resistance and support the development of nedaplatin-based approaches to cancer therapy.The B-cell lymphoma 2 (Bcl-2) family members serve as primary regulators of apoptosis and include both pro-and anti-apoptotic molecules (9). Overexpression of anti-apoptotic Bcl-2 family proteins has been associated with chemotherapy resistance in multiple human cancers (10). Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic protein in the Bcl-2 family, is frequently observed in numerous tumor types and contributes to chemotherapeutic resistance (11).ABT-737 is a small molecule inhibitor of Bcl-2 family proteins. It can bind Bcl-2 and B-cell lymphoma-extra large (Bcl-xL) with high affinity. ABT-737 has shown single agent and combination therapy efficacy against multiple myeloma, acute myeloid leukemia, lymphoma and solid tumor...

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The serine protease Omi/HtrA2: a second mammalian protein with a Reaper-like function

Cited by 47 publications

References 13 publications

TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

Mitochondrial Membrane Permeabilization in Cell Death

Nedaplatin enhanced apoptotic effects of ABT-737 in human cancer cells via Mcl-1 inhibition

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