Aging-Related Changes in Cell Death and Cell Survival Pathways and Implications for Heart Failure Therapy

We recently identified a novel signaling molecule, TAK1 (TGFβ-activated kinase 1, also known as MAP3K7), as a key regulator of the hypertrophic signaling network. Importantly, TAK1 is activated in mouse models of heart failure as well as in diseased human myocardium. Here, we defined a previously unidentified, novel role for TAK1 in promoting cardiac cell survival and homeostasis using cardiac-specific gene-targeted mice. Indeed, cardiac-specific ablation of TAK1 in mice using a Cre-LoxP system showed enhanced pathological cardiac remodeling and massive cell death, and these mice gradually developed heart failure and spontaneous death. Remarkably, ablation of TNF receptor 1 (TNFR1) largely rescued the pathological phenotype of TAK1-deficient mice, preventing early lethality and cardiac fibrosis, suggesting that TNFR1 signaling is critical in mediating adverse remodeling and heart failure associated with TAK1 deficiency. Genetic or pharmacological inactivation of TAK1 in cardiomyocytes markedly induced programmed necrosis and apoptosis in response to TNFα. Conversely, overexpression of the constitutively active TAK1 mutant, or TAK1 plus its activator TAB1, protected cardiomyocytes from TNFα-induced cell death. Mechanistically, inactivation of TAK1 promoted formation of the necroptotic cell death complex consisting of RIP1, RIP3, caspase 8, and FADD. Genetic ablation of RIP1, RIP3, caspase 8, or FADD largely blocked TNFα-induced cell death in TAK1-deficient cells, whereas deletion of Bax/Bak or cyclophilin D showed no effects. Further, IKK/NFκB-mediated cell survival signaling was greatly impaired in TAK1-deficient cardiomyocytes. Taken together, our data indicate that TAK1 functions as a critical “molecular switch” in TNFα-induced programmed necrosis in cardiomyocytes, by interacting with the RIP1/3-caspase 8-FADD cell death pathway as well as the IKK-NFκB cell survival pathway. These findings thus define an important TAK1-mediated cardio-protective signaling network in the heart, which may suggest new therapeutic strategies in the treatment of heart disease.

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Zinc Deficiency Induced Cell Death as a Consequence of Cell Cycle Inhibition and Inactivation of Cell Survival Pathways

The FASEB Journal ◽

10.1096/fasebj.20.5.a996 ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

Brad J. Niles ◽

Lynn A. Hanna ◽

Tony Y. Momma ◽

Michael S. Clegg ◽

Carl L. Keen

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Survival ◽

Zinc Deficiency ◽

Survival Pathways ◽

Cell Cycle Inhibition

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The cytotoxic type 3 secretion system 1 ofVibriorewires host gene expression to subvert cell death and activate cell survival pathways

Science Signaling ◽

10.1126/scisignal.aal4501 ◽

2017 ◽

Vol 10 (479) ◽

pp. eaal4501 ◽

Cited By ~ 8

Author(s):

Nicole J. De Nisco ◽

Mohammed Kanchwala ◽

Peng Li ◽

Jessie Fernandez ◽

Chao Xing ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Cell Survival ◽

Secretion System ◽

Host Gene Expression ◽

Survival Pathways ◽

Type 3 Secretion System ◽

Activate Cell ◽

System 1 ◽

Type 3

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Survival- and Death-Promoting Events after Transient Cerebral Ischemia: Phosphorylation of Akt, Release of Cytochrome C, and Activation of Caspase-Like Proteases

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199910000-00009 ◽

1999 ◽

Vol 19 (10) ◽

pp. 1126-1135 ◽

Cited By ~ 194

Author(s):

Yi-Bing Ouyang ◽

Ying Tan ◽

M. Comb ◽

Chun-Li Liu ◽

M. E. Martone ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Cytochrome C ◽

Western Blot ◽

Cell Survival ◽

Microscopic Study ◽

Laser Scanning ◽

Transient Cerebral Ischemia ◽

Survival Pathways ◽

Cyt C

Release of cytochrome c (cyt c) into cytoplasm initiates caspase-mediated apoptosis, whereas activation of Akt kinase by phosphorylation at serine-473 prevents apoptosis in several cell systems. To investigate cell death and cell survival pathways, the authors studied release of cyt c, activation of caspase, and changes in Akt phosphorylation in rat brains subjected to 15 minutes of ischemia followed by varying periods of reperfusion. The authors found by electron microscopic study that a portion of mitochondria was swollen and structurally altered, whereas the cell membrane and nuclei were intact in hippocampal CA1 neurons after 36 hours of reperfusion. In some neurons, the pattern of immunostaining for cyt c changed from a punctuate pattern, likely representing mitochondria, to a more diffuse cytoplasmic localization at 36 and 48 hours of reperfusion as examined by laser-scanning confocal microscopic study. Western blot analysis showed that cyt c was increased in the cytosolic fraction in the hippocampus after 36 and 48 hours of reperfusion. Consistently, caspase-3–like activity was increased in these hippocampal samples. As demonstrated by Western blot using phosphospecific Akt antibody, phosphorylation of Akt at serine-473 in the hippocampal region was highly increased during the first 24 hours but not at 48 hours of reperfusion. The authors conclude that transient cerebral ischemia activates both cell death and cell survival pathways after ischemia. The activation of Akt during the first 24 hours conceivably may be one of the factors responsible for the delay in neuronal death after global ischemia.

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Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00200.2015 ◽

2015 ◽

Vol 309 (4) ◽

pp. H676-H684 ◽

Cited By ~ 17

Author(s):

Shaiban Jubair ◽

Jianping Li ◽

Heather M. Dehlin ◽

Edward J. Manteufel ◽

Paul H. Goldspink ◽

...

Keyword(s):

Cell Death ◽

Substance P ◽

Cell Survival ◽

Receptor Antagonist ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Cellular Damage ◽

Myocardial Cells ◽

Akt Inhibitor ◽

Survival Pathways

Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT.

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Tocotrienols Modulate a Life or Death Decision in Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms20020372 ◽

2019 ◽

Vol 20 (2) ◽

pp. 372 ◽

Cited By ~ 6

Author(s):

Shiau-Ying Tham ◽

Hwei-San Loh ◽

Chun-Wai Mai ◽

Ju-Yen Fu

Keyword(s):

Cell Death ◽

Cell Survival ◽

Anticancer Agents ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Promising Alternative ◽

Cancer Cell Death ◽

Survival Pathways ◽

Cell Death Mechanisms ◽

A Minor

Malignancy often arises from sophisticated defects in the intricate molecular mechanisms of cells, rendering a complicated molecular ground to effectively target cancers. Resistance toward cell death and enhancement of cell survival are the common adaptations in cancer due to its infinite proliferative capacity. Existing cancer treatment strategies that target a single molecular pathway or cancer hallmark fail to fully resolve the problem. Hence, multitargeted anticancer agents that can concurrently target cell death and survival pathways are seen as a promising alternative to treat cancer. Tocotrienols, a minor constituent of the vitamin E family that have previously been reported to induce various cell death mechanisms and target several key survival pathways, could be an effective anticancer agent. This review puts forward the potential application of tocotrienols as an anticancer treatment from a perspective of influencing the life or death decision of cancer cells. The cell death mechanisms elicited by tocotrienols, particularly apoptosis and autophagy, are highlighted. The influences of several cell survival signaling pathways in shaping cancer cell death, particularly NF-κB, PI3K/Akt, MAPK, and Wnt, are also reviewed. This review may stimulate further mechanistic researches and foster clinical applications of tocotrienols via rational drug designs.

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A ligand-independent androgen receptor function protects from inositol hexakisphosphate-induced cell death

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14566 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14566-14566

Author(s):

J. Diallo ◽

B. Péant ◽

L. Lessard ◽

N. Delvoye ◽

C. Le Page ◽

...

Keyword(s):

Cell Death ◽

Androgen Receptor ◽

Cell Survival ◽

Cell Line ◽

Dna Fragmentation ◽

Cell Lines ◽

Caspase 3 ◽

Wild Type ◽

Survival Pathways ◽

Pc3 Cells

14566 Background: The androgen receptor (AR) is often aberrantly expressed or activated in hormone-refractory (HR) prostate cancer (PCa). Though it is not clear whether this is directly linked to AR expression, various cell survival pathways are over-activated in HR-PCa, which is characterized by its poor clinical outcome and resistance to available therapies. Inositol hexakisphosphate (IP6) is a phytochemical anti-cancer agent, which we have found to be more effective in PCa cell lines that do not express the AR. Our goal was to address the mechanism of IP6-induced cell death and to evaluate if and how the AR may interfere with its activity. Methods: We used LNCaP, DU145, 22Rv1 as well as wild-type PC3 and AR-expressing PC3 (PC3AR) cell lines to assess the metabolic toxicity of IP6 by WST-1 assay in normal, androgen-supplemented, and androgen-depleted cell culture conditions. A siRNA targeting the androgen receptor (AR) was used to control for genuine AR-mediated effects in the PC3/PC3AR cell lines. Apoptosis was quantified using fluorogenic caspase-3 assays as well as quantitative DNA fragmentation assays. Expression of a variety of genes involved in apoptosis and cell survival pathways was evaluated by real time PCR. Results: While the activity of IP6 was not modulated by the presence of androgens for any cell line, PC3AR cells were significantly more resistant to IP6 than wild-type PC3 cells according to WST-1, caspase-3 and DNA fragmentation assays (p < 0.05). Down-regulation of the AR in the PC3AR cell line resulted in increased metabolic toxicity of IP6 on these cells (p < 10−5). Although treatment with IP6 resulted in the up-regulation of the pro-apoptotic genes Puma, Noxa, as well as of IRF-2 and IkB-αλπηα in PC3 cells, this did not occur in PC3AR cells (p < 0.05). Conclusion: We conclude that, at least in PC3/PC3AR, cells IP6 sensitivity is linked to a ligand-independent function of the AR. To our knowledge, this is the first report of a ligand-independent AR function involved in resistance to a cytotoxic compound. Establishing the molecular details of this novel function is a major part of our ongoing research. No significant financial relationships to disclose.

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