Impaired Apoptotic Responses Speed Up Carcinogenesis

Programmed cell death, or apoptosis, is one of the most extensively studied topics in the areas of basic biology and cancer. The apoptotic cell is characterized by membrane blebbing, cell shrinking, cytosolic and/or nuclear condensation, and breakdown of chromosomal DNA. Apoptosis is vital to life in multicellular organisms during embryonic development and to help the removal of damaged cells in an orderly way to shape the organs and maintain adequate immune and neural cell populations. Upon invasion of exogenous pathogens, apoptosis is an important process to eliminate pathogendamaged cells. Therefore, the cellular apoptotic response has to be tightly regulated, as too little or too much apoptosis will lead to developmental deficiency, autoimmune response, or cancer.

Apoptosis differs from necrotic cell death not only morphologically but also biochemically. A key event in apoptosis is the cascade activation of cysteine aspartyl proteases, namely caspases, that implement cell apoptosis by cleaving substrates. More than one dozen caspases have been identified in mammalian cells. All caspases are synthesized as enzymatically inert zymogens under normal conditions. In the case of Fas ligand- or TNFa-induced "extrinsic" apoptosis, procaspase 8 is recruited to the intracellular domain of Fas or the TNFa receptor through death domain-containing proteins. Such recruitment activates caspase 8.42 Many stimuli, especially ROS, induce "intrinsic" apoptosis by mitochondrial damage that releases cytochrome c and causes the subsequent activation of caspase 9 through the association of Apaf-1,43,44 Both activated caspase 8 and caspase 9 are capable of activating caspase 3 by cleavage and removal of the N-terminal prodomain. The substrate specificity of distinct caspases is determined by the surrounding amino acids of the cleavage site after aspartate (Asp) residues. Although more than 100 cellular proteins have been identified as substrates for caspases, only a restricted set of proteins are cleaved by caspases at a specific stage of apoptosis.45 The typical substrates of caspases include nuclear proteins, cytoskeleton proteins, protein kinases, proteases, cytokines, and several apoptotic regulatory proteins. The caspase cleavage usually results in loss of biological activity of target proteins. However, in many cases caspase cleavage will activate the function of proteins by removing a negative regulatory domain or inactivating a suppressive subunit.

Increase of survival signals and decrease of death signals are common strategies used by various types of tumors to escape apoptosis. Many tumor cells overexpress survival factors, such as insulin-like growth factor (IGF-I) and IGF-II, that promote cells for autonomous proliferation.46 Similarly, a strong anti-apoptotic serine/threonine kinase, Akt, is overactivated in certain tumor cells due to the loss of the suppressor of Akt function, PTEN.47 Furthermore, some anti-apoptotic proteins, such as Bcl-2 and Bcl-xl, which exhibit their roles through stabilization of mitochondria, are increased in several types of tumors. However, perhaps the most important factor for the avoidance of apoptosis of tumors is the improper function of transcription factors, including E2F1, AP-1, and NF-kB.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment