Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor ...cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments.
Fractional killing is the main cause of tumour resistance to chemotherapy. This phenomenon is observed even in genetically identical cancer cells in homogeneous microenvironments. To understand this ...variable resistance, here we investigate the individual responses to TRAIL in a clonal population of HeLa cells using live-cell microscopy and computational modelling. We show that the cellular mitochondrial content determines the apoptotic fate and modulates the time to death, cells with higher mitochondrial content are more prone to die. We find that all apoptotic protein levels are modulated by the mitochondrial content. Modelling the apoptotic network, we demonstrate that these correlations, and especially the differential control of anti- and pro-apoptotic protein pairs, confer mitochondria a powerful discriminatory capacity of apoptotic fate. We find a similar correlation between the mitochondria and apoptotic proteins in colon cancer biopsies. Our results reveal a different role of mitochondria in apoptosis as the global regulator of apoptotic protein expression.
Although the expression of p27 has been regarded as a prognostic parameter in human liver cancer since the implication of decreased p27 expression levels in the genesis and progression of ...hepatocellular carcinoma (HCC), the molecular mechanism linking p27 deficiency and HCC development is still unclear. Here, we report an increase in tumorigenesis and progression as well as an enhanced inflammatory response in p27 deficient mice (p27 super(-/-)) and hypothesize the possible mechanism. We show that p27 super(-/-) mice display increased proliferation and decreased apoptosis of tumor cells, accompanied by an increase in the serum inflammatory cytokines IL-6 and TNF-alpha. Furthermore, our data indicated that the increased number and signal transducers and activator of transcription 3 (STAT3) phosphorylation status of infiltrated inflammatory cells was accompanied by increased IL-6 and TNF-alpha mRNA levels in tumor and normal liver tissue in the p27 super(-/-) mice. Moreover, using tumor cell and splenocytes co-culture and tumor homologous transplantation, we validated our hypothesis in vitro and in vivo. Collectively, these data demonstrate that the loss of p27 promotes carcinogens-induced HCC genesis and progression via the elevation of inflammatory cytokines and the augmented activation of STAT3 signaling in tumor cells and infiltrated inflammatory cells. Altogether, the loss of the cyclin kinase inhibitor p27, traditionally regarded as a consequence of DNA damage, can in turn promote HCC progression through enhancing the inflammatory response, potentially representing a promising therapeutic target in the prevention of HCC genesis and progression. J. Cell. Physiol. 228: 1967-1976, 2013. copy 2013 Wiley Periodicals, Inc.
The cardiomyocyte apoptosis plays a critical role in the development of myocardial injury after ischemia and reperfusion. Thus, alteration of the major apoptosis-regulatory factors during myocardial ...ischemiaareperfusion is expected to have favorable cardioprotective effects. Herein, we report ischemicareperfused myocardial infarction (MI) repair with siRNA against Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), which is known as a key factor involved in regulating the progress of apoptosis in many cell types. A low molecular weight polyethyleneimine modified with deoxycholic acid (PEI1.8aDA)-based delivery strategy was suggested for the cardiac application of SHP-1 siRNA to overcome the poor gene delivery efficiency to myocardium due to the highly charged structures of the compact cardiac muscles. The PEI1.8aDA conjugates formed stable nanocomplexes with SHP-1 siRNA via electrostatic and hydrophobic interactions. The PEI1.8aDA/SHP-1 siRNA polyplexes effectively silenced SHP-1 gene expression in cardiomyocytes, leading to a significant inhibition of cardiomyocyte apoptosis under hypoxia. In comparison to conventional gene carriers, relatively large amounts of siRNA molecules remained after treatment with the PEI1.8aDA/SHP-1 siRNA polyplexes. Cardiac administration of the PEI1.8aDA/SHP-1 siRNA polyplexes resulted in substantial improvement in SHP-1 gene silencing, which can be explained by the enhancement of cardiac delivery efficiency of the PEI1.8aDA conjugates. In addition, in vivo treatment with the PEI1.8aDA/SHP-1 siRNA polyplexes induced a highly significant reduction in myocardial apoptosis and infarct size in rat MI models. These results demonstrate that the PEI1.8aDA/SHP-1 siRNA polyplex formulation is a useful system for efficient gene delivery into the compact myocardium that provides a fundamental advantage in treating ischemicareperfused MI.
Reactive oxygen species (ROS) are products of normal metabolism and xenobiotic exposure, and depending on their concentration, ROS can be beneficial or harmful to cells and tissues. At physiological ...low levels, ROS function as “redox messengers” in intracellular signaling and regulation, whereas excess ROS induce oxidative modification of cellular macromolecules, inhibit protein function, and promote cell death. Additionally, various redox systems, such as the glutathione, thioredoxin, and pyridine nucleotide redox couples, participate in cell signaling and modulation of cell function, including apoptotic cell death. Cell apoptosis is initiated by extracellular and intracellular signals via two main pathways, the death receptor- and the mitochondria-mediated pathways. Various pathologies can result from oxidative stress-induced apoptotic signaling that is consequent to ROS increases and/or antioxidant decreases, disruption of intracellular redox homeostasis, and irreversible oxidative modifications of lipid, protein, or DNA. In this review, we focus on several key aspects of ROS and redox mechanisms in apoptotic signaling and highlight the gaps in knowledge and potential avenues for further investigation. A full understanding of the redox control of apoptotic initiation and execution could underpin the development of therapeutic interventions targeted at oxidative stress-associated disorders.
Apoptosis signaling by death receptors Schulze‐Osthoff, Klaus; Ferrari, Davide; Los, Marek ...
European journal of biochemistry,
06/1998, Letnik:
254, Številka:
3
Journal Article
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Death receptors have been recently identified as a subgroup of the TNF‐receptor superfamily with a predominant function in induction of apoptosis. The receptors are characterized by an intracellular ...region, called the death domain, which is required for the transmission of the cytotoxic signal. Currently, five different such death receptors are known including tumor necrosis factor (TNF) receptor‐1, CD95 (Fas/APO‐1), TNF‐receptor‐related apoptosis‐mediated protein (TRAMP) and TNF‐related apoptosis‐inducing ligand (TRAIL) receptor‐1 and ‐2. The signaling pathways by which these receptors induce apoptosis are rather similar. Ligand binding induces receptor oligomerization, followed by the recruitment of an adaptor protein to the death domain through homophilic interaction. The adaptor protein then binds a proximal caspase, thereby connecting receptor signaling to the apoptotic effector machinery. In addition, further pathways have been linked to death receptor‐mediated apoptosis, such as sphingomyelinases, JNK kinases and oxidative stress. These pro‐apoptotic signals are counteracted by several mechanisms which inhibit apoptosis at different levels. This review summarizes the current and rapidly expanding knowledge about the biological functions of death receptors and the mechanisms to trigger or to counteract cell death.
Cancer is typically a consequence of imbalance between cell death and proliferation in a way favorable to cell proliferation and survival. Most conventional cancer therapies are based on targeting ...rapidly growing cancerous cells to block growth or enhance cell death, thereby, restoring the balance between these processes. In many instances, malignancies that develop resistance to current treatment modalities, such as chemotherapy, immunotherapy, and radiotherapy often present the greatest challenge in subsequent management of the patient. Studies have shown that under normal circumstances, cells utilize different death mechanisms, such as apoptosis (programmed cell death), autophagy, mitotic catastrophe, and necrosis to maintain homeostasis and physiological integrity of the organism, but these processes often appear to be altered in cancer. Thus, in recent years developing various strategies for administration of cytotoxic chemotherapeutics in combination with apoptosis-sensitizing reagents is receiving more emphasis. Here, we review the properties of the anti-apoptotic protein, survivin, a member of the inhibitor of apoptosis protein (IAP) family and the clinical feasibility and anti-cancer potential of drugs targeting this protein. We also discuss some key points and concerns that should be taken into consideration while developing drugs that target apoptotic proteins, such as survivin.
Our previous studies have demonstrated that phytoestrogen alpha-zearalanol (alpha-ZAL) possesses potential benefits in alleviating cell apoptotic death just like oestrogen. However, the underlying ...mechanism is not fully understood. This study was designed to test the hypothesis that the neuroprotective effect of alpha-ZAL is mediated by oestrogen receptor (ER) as alpha-ZAL owns the benzene ring structure may interact with ER. The present results showed a significant increase in apoptosis in differentiated PC12 cells after a 24-hr exposure to amyloid beta-peptide fragment 25-35 (Abeta25-35), accompanied by decreasing of bcl-2 expression and increasing bax expression, whereas a pre-treatment with alpha-ZAL ameliorated these changes induced by Abeta25-35. In addition, the alpha-ZAL-mediated cytoprotection was abrogated by ERalpha antagonist but not by ERbeta antagonist. In summary, these data suggest that alpha-ZAL intervenes against Abeta-induced apoptosis via intersecting bcl-2-bax apoptotic pathway in an ERalpha-sensitive manner.