Apoptosis refers to a process in which there is programmed cell death in multicellular organisms. There are characteristic changes in cells and cell death caused by biochemical events. The changes include cell shrinkage, bebbling, chromosomal DNA, and global mRNA decay, chromatin condensation and nuclear fragmentation. Apoptosis leads to death of 50 to 70 billion cell in a day in an average human adult.
Between 20 to 30 billion cells in every day in a child 8 to 14 years of age (Ouyang, et al., 2012).Apoptosis defect can lead to autoimmunity or cancer, whereas enhanced apoptosis results in degenerative diseases. Signals from apoptosis contribute in safeguarding the integrity of genes whereas defective apoptosis may lead to carcinogenesis. Signals produced by apoptosis are usually complicated and are controlled at different levels.
Carcinogenesis signals regulate central control points of apoptosis. Apoptosis pathways include FLICE-inhibitory protein (c-FLIP) and inhibitory of apoptosis proteins (IAP).Tumor cells use different molecular mechanisms to acquire apoptotic agents resistance and suppress apoptosis, for instance, antiapoptotic proteins expression, that is Bcl-2 or through down regulation or proapoptotic mutation such as BAX. In this study we offer the main regulatory molecules that control the basic mechanisms, intrinsic and extrinsic of apoptosis regular cells.
Carcinogenesis development through defective apoptotic pathway or its convergence have been discussed. Some molecules that are target to stimulate apoptosis in various cancer have been listed. Here, a brief discussion on the development of some cancer treatment strategies has been made that target apoptotic inhibitors such as IAPs, c-FLIP and Bcl-2 family proteins for apoptosis induction.
Apoptosis refers to a process of tightly programmed cell death with distinct ge...
netic and biochemical pathways that have a vital role in homeostasis and development in normal tissues. It leads to removal of unwanted and unnecessary cells to ensure the healthy balance between cell death and cell survival in metazoan. It is important to animals such as long-lived mammals that require to integrate several physiological and pathological death signals.Insufficient apoptosis has been indicated to manifest as autoimmunity or cancer, whereas accelerated cell death occur in chronic and acute degenerative diseases, infertility and immunodeficiency.
Under several stressful conditions such as precancerous lesions, DNA damage activation checkpoint pathway may help to remove DNA damaged cells which are potentially harmful through apoptosis induction to inhibit carcinogenesis. Therefore, the apoptotic signals assist in safeguarding the integrity of genes whereas dysregulation of apoptotic pathways promote tumor genesis as well as rendering cancer cells resistant to treatment.
Hence, apoptosis evasion is the main hallmark for cancer. Cancer cells harbor alterations that lead to impaired apoptotic signaling, hence facilitating development and metastasis of tumor. An overview of mechanisms through which main regulatory molecules regulate apoptosis in regular cells and apoptotic dysregulation models based on alteration of their function that facilities apoptosis evasion in cancer cells has been provided.
Apoptosis defects play critical roles in pathogenesis of tumors allowing survival of neoplastic cells over intended lifespans, the desire for exogenous survival factors is subverted and provision of protection from hypoxia and oxidative stress as the tumor mass grows.it gives time for genetic alterations accumulations that deregulate cell proliferation, promote angiogenesis, interfering with differentiation and increase invasiveness in tumo
progression (West, et al., 2014). Apoptosis defects have been considered to be important complements in proto-oncogene activation, as several deregulated oncoproteins promote cell division they also trigger apoptosis for instance E1a, Cyclin-D1 and Myc.
Defects in chromosome segregation and/or DNA repair usually trigger cell death as a defense mechanism to eradicate genetically unstable cells and these death mechanism defect allow survival of cells that are genetically unstable, provide opportunity to select progressively aggressive clones and also promote tumor genesis. There are various molecular mechanisms with which tumor cells use apoptosis suppression.
Tumor cells become resistant to apoptosis through the expression of ant apoptotic proteins including Bcl-2 or through downregulation or proapoptotic proteins mutation e.g. BAX. The expression of both BAX and Bcl-2 is regulated through the p53 tumor gene suppression.Bcl-2 overexpression occur in different forms of lymphoma human B-cell. This example gives the first and strongest lines of prove that cancer is contributed by failure of cell death.
Apoptosis defects allow survival of epithelial cells in a suspended state, with no attachment to extracellular matrix which leads to metastasis. Resistance to the immune system is also promoted including several weapons of natural killer (NK) cells and cytolytic T cells (CTLs)used to attack tumors that are based on apoptosis machinery integrity (Curcoran, et al., 2013). Defects associated with cancer in apoptosis play an important role in resistance treatment with conventional therapies such as radiotherapy and chemotherapy increasing cell death threshold and therefore need high doses for tumor killing agents.
Thus defective and dysregulated apoptosis regulation is an important factor in tumor biology. Successful elimination of cancer cells through nonsurgical methods is ultimately approached through induction of apoptosis. Thus, all designers of cancer drugs to try either to rectify defective apoptotic mechanism or activated inactivated one. Therefore, all cytotoxic anticancer therapies in clinical use nowadays induce malignant cells apoptosis when they work. Knowledge on molecular mechanisms of apoptosis their defective stateprovides a room for new class of target therapy.
Proteases called caspases is known to cause apoptosis by specifically targeting cysteine aspartyl. After receiving some signals which are specific instructing the cell to undergo apoptosis several distinctive changes take place in the cell. Protein family referred to as caspases normally activated in apoptosis early stages. These protein cleave important cellular components which are required for cells to function normally such as structural proteins in nuclear proteins and cytoskeleton. For example DNA repair enzymes.
Also caspases can activate some degradative enzymes like DNases, which start DNA cleavage at the nucleus. Distinctive morphology is usually displayed by apoptotic cells during apoptotic process. Normally the cell begin by shrinking following actin filaments and lamins cleavage in cytoskeleton. Chromatin undergo apoptotic breakdown in the nucleus which results in nuclear condensation and a horse shoe like appearance.
Cells shrink and package themselves in a form that can be removed by microphages. The phagocytic cells have the role of clearing apoptotic cells from tissues in tidy and clean fashion to prevent the various problems linked to necrotic cell death.Apoptotic cells phagocytosis through microphages is promoted by changes in plasma membrane caused by macrophage response.(Knizhnik, et al., 2013). One of these changes is the phosphatidyserine translocation to