Caspase-2 protects against oxidative stress in vivo

Shalini, Sonia; Puccini, Joseph; Wilson, Christopher M.; Finnie, John; Dorstyn, Loretta; Kumar, Sharad

doi:10.1038/onc.2014.413

Cited by 33 publications

(34 citation statements)

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“…One reason for the advanced tumorigenic state may be higher ROS levels in Casp2 − / − mice leading to increased oxidative stress-induced DNA damage. We have shown earlier that Casp2 −/− mice experience excessive oxidative stress with ageing and oxidative stress response 5,23 and here again show increased susceptibility to more oxidative DNA and protein damage after DEN injection. Sirtuins contribute to the response to oxidative stress and the lower Sirt1 and Sirt3 activities in DEN-injected Casp2 − / − mice may in part contribute to increased susceptibility to DEN-induced damage.…”

Section: Discussionsupporting

confidence: 73%

“…1-4 Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.Hepatocellular carcinoma (HCC) is among the most common cancers and is the second leading cause of cancer-related deaths worldwide. 7 Development of HCC is multifaceted progressing from DNA damage to dysplasia, adenoma development and malignant transformation of hepatocytes.…”

mentioning

confidence: 99%

“…[1][2][3][4] Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.…”

mentioning

confidence: 99%

“…21,22 Caspase-2 deficiency in mice results in metabolic perturbations and aged caspase-2 mice show increased oxidative stress and DNA damage. 5,21,23 DEN-induced tumour formation involves the generation of DNA adducts, 10 and human HCC is commonly associated with genomic instability. 24 These observations, combined with the known tumour suppressor role in lymphoma and MMTV-driven mammary carcinoma, suggest a possible role of caspase-2 in HCC.…”

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confidence: 99%

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Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damageinduced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2 −/− ) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2 −/− mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2 −/− mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis. The initiator caspase, caspase-2, has recently emerged as a tumour suppressor with loss of this protein being associated with increased lymphomagenesis in ATM-deficient mice and Eμ-Myc transgenic mice, and MMTV/c-neu-driven mammary carcinoma. 1-4 Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.Hepatocellular carcinoma (HCC) is among the most common cancers and is the second leading cause of cancer-related deaths worldwide. 7 Development of HCC is multifaceted progressing from DNA damage to dysplasia, adenoma development and malignant transformation of hepatocytes. 7,8 The major risk factors of HCC include viral hepatitis, excessive alcohol consumption, carcinogens and metabolic diseases. 7,8 Despite this, the molecular causes of the disease are relatively less understood. Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. 7-10 It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. 11-13 While loss of apoptosis would indirectly favour proliferation, this is not universa...

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Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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“…194 Paraquat-induced pulmonary lesions in aged caspase-2 knockout mice were more severe and associated with hepatocyte karyomegaly. 195 It was recently shown that the increase in mitochondrial ROS in aged caspase-2 knockout mice is associated with mitochondrial complex-III activity. 196 The early-aging phenotype observed in caspase-2 knockout is distinct and involves non-apoptotic properties of this protease including its role in oxidative stress.…”

Section: Caspase Activation During Agingmentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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Molecular Cell Biology of Apoptosis and Necroptosis in Cancer

Dillon

Green

2016

Apoptosis in Cancer Pathogenesis and Anti-Cancer Therapy

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Cell death is a major mechanism to eliminate cells in which DNA is damaged, organelles are stressed, or oncogenes are overexpressed, all events that would otherwise predispose cells to oncogenic transformation. The pathways that initiate and execute cell death are complex, genetically encoded, and subject to significant regulation. Consequently, while these pathways are often mutated in malignancy, there is considerable interest in inducing cell death in tumor cells as therapy. This chapter addresses our current understanding of molecular mechanisms contributing to two cell death pathways, apoptotic cell death and necroptosis, a regulated form of necrotic cell death. Apoptosis can be induced by a wide variety of signals, leading to protease activation that dismantles the cell. We discuss the physiological importance of each apoptosis pathway and summarize their known roles in cancer suppression and the current efforts at targeting each pathway therapeutically. The intricate mechanistic link between death receptor-mediated apoptosis and necroptosis is described, as well as the potential opportunities for utilizing necroptosis in the treatment of malignancy.

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Caspase-2 protects against oxidative stress in vivo

Cited by 33 publications

References 50 publications

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Old, new and emerging functions of caspases

Molecular Cell Biology of Apoptosis and Necroptosis in Cancer

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