**4. Role of apoptosis in cancer**

Cells can die in variety of ways which includes apoptosis, necrosis, mitotic catastrophe, senescence, and autophagy. Of these different modes of cell death, apoptosis is active, programmed and genetically controlled. While physiological apoptosis helps to eliminate genetically altered cells, defective apoptosis is intimately connected with cancer pathogenesis [30]. Apoptotic signaling regulation is important to preserve a proper balance between cell death and cell survival. It is also important in maintaining genome integrity. The Apoptosis evasion is a prominent hallmark of cancer and cancer cells can use a number of diverse strategies to evade apoptosis. The disruption in the balance between pro- and anti-apoptotic proteins contributes to carcinogenesis [31]. It may be due to the reducing apoptosis in malignant cells [30]. For example, the imbalance between pro- and anti-apoptotic Bcl-2 proteins, its genetic and epigenetic alterations, can promote cancer cell survival. The elevated levels of anti-apoptotic family members is a distinct mechanism of apoptosis dysregulation in cancer. The anti-apoptotic proteins are widely over-expressed in cancer cells to overcome stress signals. Over-expression of anti-apoptotic Bcl-2 family proteins is often correlated with recurrence, poor prognosis, and resistance to cancer therapeutics [11].

miRNAs are a class of non-coding RNAs that regulate post-transcriptional gene expressions and silence target mRNAs. miRNAs dysregulation are associated with different human cancers and microRNAs (miRNAs) can function as oncogenes as well as tumor suppressors and their dysregulation are associated with many different human cancers.. miRNAs target different mRNAs and act as anti-apoptotic or pro-apoptotic regulatots that involved in the apoptotic pathways [32]. For example, miR-15/16 targets the anti apoptotic factor (Bcl-2). In many cancers, the mostly upregulated miRNA is anti-apoptotic miRNA-21. It targets the programmed cell death 4 gene (PCD 4 gene or PDCD4), tropomyosin 1 (TPM1), and the phosphatase and tensin homolog (PTEN), to modulate apoptosis. The application of anti-microRNAs imitate may act as a potent therapeutic strategy to inhibit key molecular signaling pathways that are present in cancer [32, 33].

Cancer cells often show dysregulated expression patterns of diverse long noncoding RNAs (lncRNAs) in specific kinds of tumors. Therefore, their upexpression or down-regulation in cancer cells often sensitizes cells to apoptotic treatments.

#### *Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97536*

They also induce and modulate apoptosis. Therefore, targeting lncRNAs in cancer cells can be utilized for cancer treatment. Cellular-FLICE inhibitory protein (c-FLIP) is a critical negative regulator of the apoptotic pathway. The apoptosis regulation due to c-FLIP, mediated by the death receptors Fas, TNF-R1, DR4 and DR5. It exists in three isoforms that are derived from diverse mRNA splice variants. These splice variants are transcribed under the same promoter, namely c-FLIPL, c-FLIPS, and c-FLIPR. The three isoforms of c-FLIP acts at the DISC level and inhibit the procaspase 8 and 10 activation. C-FLIP high expression is found in many cancers and its downexpression can restore apoptosis mediated by TRAIL Aand CD95L. Thus, c-FLIP can act as a promising target for cancer therapy [34]. c-FLIP can also induce apoptosis at low and more physiologically relevant expression levels by recruiting at the DISC to increase caspase-8 activation.

NF-kB activation by CD40 ligand or TNF-α results in overexpression of c-FLIP and the prohibition of TNFR1, Fas- and TRAIL receptors induces apoptosis. Activation of several pathways, such as mitogen-activated protein kinase (MAPK), the phosphatidylinositol-3 kinase (PI3K)/Akt, can enhance the expression of c-FLIP and can hamper apoptosis induced by death receptors [35].

IAPs increase cell survival during cellular stresses such as ER stress and prevent both intrinsic and extrinsic apoptosis. Caspases dysregulation may inhibit apoptosis and carcinogenesis. Down-regulation of different caspases has been observed in many cancers. For example, caspase-9 and caspase-3 downregulation can leads to formation of different forms of cancers such as colorectal, ovarian, breast, and cervical cancers [36, 37].
