Apoptosis anti-apoptotic

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2 during p-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9, and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein BclXL was found to be another important event during P-carotene-induced apoptosis, suggesting the presence of an extensive feedback amplification loop in P-carotene-induced apoptosis (Prasad et al., 2006). 

Mitochondrial function. NO is able to react with transition metals such as iron, including those contained within haem groups. Even at low NO concentrations there is competition between oxygen and NO for reversible binding to cytochrome c oxidase. If mitochondrial 02 is low respiration slows, which may confer anti-apoptotic benefit to the cell. As NO concentration rises and peroxynitrite is formed, electron transport is irreversibly inhibited, there is increased production of superoxide and other reactive oxygen species and apoptosis occurs. 

It should be noted here that the synthesis of sphingomyelin, the lipid whose synthesis and breakdown are most intricately involved in the process of apoptosis, is dependent on the presence of PC, since the final step in SM synthesis involves the exchange of the phosphocholine head group from PC to ceramide (see Eigure 1). Theoretically, therefore, inhibition of PC synthesis may lead to an inhibition of SM generation and an accumulation of pro-apoptotic ceramides. On the other hand, an increased breakdown of SM by SMases as frequently observed in apoptotic cells, was shown to increase the conversion of PC to anti-apoptotic DAG (Sillence and Allan, 1998, for anti-apoptotic action of DAG see below). 

This chapter describes the metabohsm of sphingosine and SIP, evidence to support their pro- and anti-apoptotic effects and their proposed sites of action on signaling processes that contribute to apoptosis and proliferation. 

Esophagus (cells of BE, a pre-neoplastic lesion) Increased resistance to DOC-induced apoptosis in BE cells compared to control cells. Increased expression of anti-apoptotic proteins Bc1-xl, and Mcl-l 47,126... 

Colon [biopsies from colonic mucosa (nontumour tissue) of patients with colon cancer] Increased resistance to DOC-induced apoptosis of colonic epithelial cells of cancer patients or increased expression of anti-apoptotic protein Bc1-xl. 1,27,28,52,127... 

Although taxanes bind to p-tubulin promoting microtubule polymerization and stabilization of the spindle complex, they serve to cause a sustained mitotic block at the metaphase/anaphase boundary. This block will occur at a lower concentration than that which is required to increase the microtubule mass (10). However, it is not completely clear how this interaction with microtubules translates into cell death. Morphologic features and the characteristic DNA fragmentation patterns seen in the setting of apoptosis have been documented in tumor cells after therapy with taxanes (10). These observations are accompanied by the phosphorylation of Bcl-2, an anti-apoptotic protein, changing the cellular balance between Bax and Bcl-2 to a status that favors apoptosis (11). 

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