**Abstract**

Skin cancer is more prevalent than any other cancer in the United States. Nonmelanoma skin cancers are the more common forms of skin cancer that affect individuals. The development of squamous cell carcinoma, the second most common type of skin cancer, can be stimulated by exposure of environmental carcinogens, such as chemical toxicants or UVB. It is developed by three distinct stages: initiation, promotion, and progression. During the initiation, the fate of DNA-damaged skin cells is determined by the homeostatic regulation of pro-apoptotic and antiapoptotic signaling pathways. The imbalance or disruption of either signaling will lead to the survival of initiated cells, resulting in the development of skin cancer. In this chapter, we will discuss signaling pathways that regulate apoptosis and the impact of their dysfunction during skin tumor initiation.

**Keywords:** apoptosis, tumor initiation, skin, carcinogen, UVB, AKT, STAT3, MAPK, TC-PTP

## **1. Introduction**

Apoptosis, also called programmed cell death, is an essential cellular process that is required to maintain tissue homeostasis by modulating various biological functions including embryonic development, cellular growth, and immunity through the elimination of unwanted cells. Apoptosis accompanies the distinct morphological changes, such as membrane blebbing, cell shrinkage, chromatin condensation, and DNA fragmentation. These morphological changes during apoptosis were first observed by John Foxton R. Kerr, Andrew H. Wyllie, and Alastair Currie in 1972 with the first description of "apoptosis" [1]. Later, the critical role of programmed cell death occurred during the development of the nematode *Caenorhabditis elegans* was elucidated with the finding of death-related genes in 1999 [2]. Three scientists – Sydney Brenner, H. Robert Horvitz, and John E. Sulston – were awarded the Nobel Prize in Physiology or Medicine in 2002 for their discovery of genes that regulate apoptosis. Since then, apoptosis has extensively been studied as a crucial biochemical mechanism for the maintenance of normal tissue function and homeostasis. Dysregulation of apoptosis has been involved in various types of human diseases including cancers and neurodegenerative diseases [3, 4].

Cells can die prematurely by injury, infection, external assault such as chemicals, or a lack of blood supply through energy-independent process of cell death, which is called by necrosis. Necrosis is an unplanned cellular death by external damage. It causes severe disorganization and rupture of subcellular structure and eventually leads to disruption of the cell membrane. Then, the exposure of cellular components of necrotic cells into the surrounding interstitial tissue results in inflammation. In contrast to necrosis, apoptotic cell death is highly ordered and energy-dependent molecular process that can eliminate unwanted and damaged cells without causing inflammation [5, 6].

Apoptosis is initiated by two different pathways: the extrinsic and the intrinsic pathways. The extrinsic pathway is mediated by the interaction of transmembrane receptors known as death receptors with their ligands. Death receptors are members of the tumor necrosis factor (TNF) gene family and share similar cysteine-rich extracellular domains and homologous intracellular cytoplasmic sequence named as the 'death domain'. The death domain of receptors transmits the death signal from the cell surface to the intracellular signaling pathways to induce apoptosis in a rapid and efficient manner. For example, the binding of Fas ligand with Fas receptor, TNFα with TNF receptor, and TNF-related apoptosis-inducing ligand (TRAIL) with TRAIL receptor 1, 2 results in the interaction of the death domain of receptor with the adaptor protein, such as Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD). The adaptor protein then associates with procaspase-8 and converts it into active caspase-8 [3, 7]. Likewise, the intrinsic pathway, which is known as the mitochondrial pathway, is activated by a broad range of exogenous and endogenous stimuli including radiation, toxins, viral infections, and oxidative stress. It modulates mitochondrial membrane potential through change of the ratio of pro-apoptotic and anti-apoptotic proteins located in the mitochondria and releases cytochrome c from the intermembrane space into the cytoplasm. Cytochrome c then forms a multi-protein complex called as the 'apoptosome' with apoptotic protease activating factor 1 (APAF1) and recruits inactive procaspase-9, which is followed by the dimerization and generation of catalytically active caspase-9 in an ATP-dependent manner [8, 9]. Initiation of both the extrinsic and intrinsic pathways can lead to the activation of executioner caspases, such as caspase-3, 6, or 7, resulting in the morphological changes of apoptosis [10]. These two apoptotic pathways are interconnected. The cleavage of pro-apoptotic protein Bid by caspase-8 can lead to its translocation to the mitochondria and result in the activation of the mitochondrial pathway [11]. Environment toxicants, such as ultraviolet B (UVB) radiation and chemical carcinogens, can cause severe DNA damage, which activates the intrinsic pathway in skin [12, 13]. UVB radiation can also activate the extrinsic pathway by inducing Fas receptor by p53 activation, promoting the association of TNF receptor 1 with TNF receptor-associated factor-2 (TRAF-2), or inhibiting the interaction of TRAIL receptors with decoy receptors that serve as their negative binding partners for apoptosis (**Figure 1**) [14–17].

In intrinsic pathway, mitochondrial outer membrane permeability is regulated by pro-apoptotic or anti-apoptotic proteins of B-cell lymphoma 2 (Bcl-2) family. A total of 25 genes in the Bcl-2 family have been identified. The pro-apoptotic proteins of Bcl-2 family include Bax, Bak, Bid, Bim, Bad, Noxa, Bmf, and Puma. The anti-apoptotic proteins of Bcl-2 family include Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and BAG. Altered expression of Bcl-2 family proteins has been involved in various diseases including cancer [18–21].

Skin, the largest organ of the human body, is continuously exposed to environmental assaults. Exposure of skin to the chemical carcinogens or UVB radiation induces a mutation in critical gene or genes and forms specific carcinogen-DNA adducts. These adducts can be repaired by DNA repair mechanism. Otherwise, they need to be removed by apoptosis. Defected apoptosis by genetic abnormalities and

*Regulation of Apoptosis during Environmental Skin Tumor Initiation DOI: http://dx.doi.org/10.5772/intechopen.97542*

#### **Figure 1.**

*Mechanisms of apoptosis induced by environmental carcinogens in skin. Apoptosis is initiated by two major pathways: The extrinsic and the intrinsic pathways. The extrinsic pathway is mediated by death receptors, such as Fas receptor. Upon binding to Fas ligand, Fas receptor interacts with FADD and recruits procaspase-8, which is followed by activation of caspase-8. The intrinsic pathway causes DNA damage and modulates mitochondrial membrane potential. Then, cytochrome c is released from the mitochondria into the cytoplasm. The formation of apoptosome with cytochrome c and APAF1 recruits and activates caspase-9. Activation of either caspase-8 or caspase-9 leads to the activation of executioner caspases including caspase-3, resulting in the morphological changes of apoptosis. These two pathways are also interconnected. The cleavage of bid by caspase-8 leads to its translocation to the mitochondria and activates the mitochondrial pathway. Environment toxicants, such as UVB radiation and chemical carcinogens, cause severe DNA damage and activate the intrinsic pathway in skin. UVB radiation activates the extrinsic pathway by activating death receptors and enhancing the association of death receptors with their ligands.*

subsequent imbalanced signaling pathways can cause the survival of damaged cells during the tumor initiation. These damaged cells can undergo clonal expansion during the tumor promotion and eventually develop skin cancer [22–25]. In this chapter, we will review anti-apoptotic signaling pathways – AKT, STAT3, and MAPK – and pro-apoptotic signaling pathway – protein tyrosine phosphatases (PTPs) –, which are involved in the regulation of apoptosis during skin tumor initiation.
