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Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.

ABSTRACT: Molecular mechanisms underlying apoptosis in retinitis pigmentosa, as in other neurodegenerative diseases, are still elusive, and this fact hampers the development of a cure for this blinding disease. We show that two apoptotic pathways, one from the mitochondrion and one from the endoplasmic reticulum, are coactivated during the degenerative process in an animal model of retinitis pigmentosa, the rd1 mouse. We found that both AIF and caspase-12 translocate to the nucleus of dying photoreceptors in vivo and in an in vitro cellular model. Translocation of both apoptotic factors depends on changes in intracellular calcium homeostasis and on calpain activity. Knockdown experiments defined that AIF plays the major role in this apoptotic event, whereas caspase-12 has a reinforcing effect. This study provides a link between two executor caspase-independent apoptotic pathways involving mitochondrion and endoplasmic reticulum in a degenerating neuron.

SUBMITTER: Sanges D

PROVIDER: S-EPMC1859935 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.

Sanges Daniela D Comitato Antonella A Tammaro Roberta R Marigo Valeria V

Proceedings of the National Academy of Sciences of the United States of America 20061106 46

Molecular mechanisms underlying apoptosis in retinitis pigmentosa, as in other neurodegenerative diseases, are still elusive, and this fact hampers the development of a cure for this blinding disease. We show that two apoptotic pathways, one from the mitochondrion and one from the endoplasmic reticulum, are coactivated during the degenerative process in an animal model of retinitis pigmentosa, the rd1 mouse. We found that both AIF and caspase-12 translocate to the nucleus of dying photoreceptors ...[more]

PMID: 17088543

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Project description:BackgroundBone morphogenetic proteins (BMP) are evolutionarily conserved morphogens that are reactivated in lung carcinomas. In lung cancer cells, BMP signaling suppresses AMP activated kinase (AMPK) by inhibiting LKB1. AMPK is activated by mitochondrial stress that inhibits ATP production, which is enhanced 100-fold when phosphorylated by LKB1. Activated AMPK can promote survival of cancer cells but its "hyperactivation" induces cell death. The studies here reveal novel cell death mechanisms induced by BMP inhibitors, together with agents targeting the mitochondria, which involves the "hyperactivation" of AMPK.MethodsThis study examines the synergistic effects of two BMP inhibitors together with mitochondrial targeting agents phenformin and Ym155, on cell death of lung cancer cells expressing LKB1 (H1299), LKB1 null (A549), and A549 cells transfected with LKB1 (A549-LKB1). Cell death mechanisms evaluated were the activation of caspases and the nuclear localization of apoptosis inducing factor (AIF). A769662 was used to allosterically activate AMPK. Knockdown of BMPR2 and LKB1 using siRNA was used to examine their effects on nuclear localization of AMPK. Validation studies were performed on five passage zero primary NSCLC.ResultsBoth BMP inhibitors synergistically suppressed growth when combined with Ym155 or phenformin in cells expressing LKB1. The combination of BMP inhibitors with mitochondrial targeting agents enhanced the activation of AMPK in lung cancer cells expressing LKB1. Allosteric activation of AMPK with A769662 induced cell death in both H1299 and A549 cells. Cell death induced by the combination of BMP inhibitors and mitochondrial-targeting agents did not activate caspases. The combination of drugs induced nuclear localization of AIF in cells expressing LKB1, which was attenuated by knockdown of LKB1. Knockdown of BMPR2 together with Ym155 increased nuclear localization of AIF. Combination therapy also enhanced cell death and AIF nuclear localization in primary NSCLC.ConclusionsThese studies demonstrate that inhibition of BMP signaling together with mitochondrial targeting agents induce AIF caspase-independent cell death, which involves the "hyperactivation" of AMPK. AIF caspase-independent cell death is an evolutionarily conserved cell death pathway that is infrequently studied in cancer. These studies provide novel insight into mechanisms inducing AIF caspase-independent cell death in cancer cells using BMP inhibitors. Video Abstract.

Project description:ObjectiveDiaphragmatic weakness, due to both atrophy and contractile dysfunction, is a well-documented response following prolonged mechanical ventilation. Evidence indicates that activation of the proteases calpain and caspase-3 is essential for mechanical ventilation-induced diaphragmatic weakness to occur. We tested the hypothesis that a regulatory cross-talk exists between calpain and caspase-3 in the diaphragm during prolonged mechanical ventilation. To test this prediction, we determined whether selective pharmacological inhibition of calpain would prevent activation of caspase-3 and conversely whether selective inhibition of caspase-3 would abate calpain activation.DesignAnimal study.SettingUniversity Research Laboratory.SubjectsFemale Sprague-Dawley rats.InterventionsAnimals were randomly divided into control or one of three 12-hr mechanical ventilation groups that were treated with/without a selective pharmacological protease inhibitor: 1) control, 2) mechanical ventilation, 3) mechanical ventilation with a selective caspase-3 inhibitor, and 4) mechanical ventilation with a selective calpain inhibitor.Measurements and main resultsCompared to control, mechanical ventilation resulted in calpain and caspase-3 activation in the diaphragm accompanied by atrophy of type I, type IIa, and type IIx/IIb fibers. Independent inhibition of either calpain or caspase-3 prevented this mechanical ventilation-induced atrophy. Pharmacological inhibition of calpain prevented mechanical ventilation-induced activation of diaphragmatic caspase-3 and inhibition of caspase-3 prevented activation of diaphragmatic calpain. Furthermore, calpain inhibition also prevented the activation of caspase-9 and caspase-12, along with the cleavage of Bid to tBid, all upstream signals for caspase-3 activation. Lastly, caspase-3 inhibition prevented the mechanical ventilation-induced degradation of the endogenous calpain inhibitor, calpastatin.ConclusionsCollectively, these results indicate that mechanical ventilation-induced diaphragmatic atrophy is dependent on the activation of both calpain and caspase-3. Importantly, these findings provide the first experimental evidence in diaphragm muscle that calpain inhibition prevents the activation of caspase-3 and vice versa and caspase-3 inhibition prevents the activation of calpain. These findings support our hypothesis that a regulatory calpain/caspase-3 cross-talk exists whereby calpain can promote caspase-3 activation and active caspase-3 can enhance calpain activity in diaphragm muscle during prolonged mechanical ventilation.

Dataset Information

Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.

Publications

Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.

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