Life and Death Signaling Pathways Contributing to Skin Cancer

Abstract

Apoptosis is generally regarded as a critical regulatory event in the development of malignancies in several different organ systems (Thompson, 1995). Initially, oncologists focused on alterations in rates of proliferation and cell cycle kinetics, but more recently an emphasis on apoptosis has dominated the fight against cancer (Evan and Vousden, 2001). As approximately 1,000,000 individuals in the U.S.A. develop skin cancer each year, it is important to elucidate the molecular mechanisms that govern cell survival and cell death in the epidermis (Miller and Weinstock, 1994). Moreover, given that most skin cancers occur on sun-exposed skin, the pro-apoptotic and antiapoptotic response of keratinocytes (KC) to UV light is of particular relevance to the development of skin cancer (Brash et al, 1996). Whereas both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) arise from epidermal KC, it is becoming increasingly apparent that the natural history of their development, their underlying molecular pathogenesis, and potential involvement of antiapoptotic pathways are significantly different. Nonetheless, as pointed out later in the text, significant progress is being made in our understanding of the pathophysiology of these relatively common epithelial-cell-derived neoplasms. In this review we will explore four topics: first, a review of the life and death signaling pathways operative in normal human skin that prevents premature apoptosis of KC with an emphasis on nuclear factor kappaB (NFkappaB) survival signals; second, the molecular pathways that are engaged and regulate apoptosis after normal KC are exposed to ultraviolet (UV) light; third, the apoptotic resistant mechanisms that premalignant and malignant KC utilize to avoid cell death; fourth, therapeutic strategies that can render malignant cells more susceptible to apoptosis with an emphasis on a death pathway mediated by the death ligand TRAIL.

Ultraviolet A-induced Modulation of Bcl-XL by p38 MAPK in Human Keratinocytes

“…Overexpression of Bcl-2 has been observed in basal cell carcinomas, whereas overexpression of Bcl-X L has been reported in squamous cell carcinomas of the skin (27)(28)(29)(30)(31). We investigated whether overexpression of Bcl-2 would demonstrate a similar effect as that observed with Bcl-X L overexpression.…”

“…Finally, the post-transcriptional regulation of Bcl-X L is mediated through the 3Ј-UTR and is dependent upon p38 MAPK activity. As Bcl-X L is overexpressed in squamous cell carcinoma (27) and potentially other cancer types, new insights into mechanisms regulating its expression are of great interest. In summary, we demonstrate modulation of Bcl-X L expression by UVA-induced p38 MAPK activity providing protection from apoptosis.…”

Spontaneous Squamous Cell Carcinoma Induced by the Somatic Inactivation of Retinoblastoma and Trp53 Tumor Suppressors

“…1 In addition, chemical carcinogenesis protocols in these mice result in reduced number of tumors, which also show smaller size and increased malignant conversion (19). This is mediated, at least in part, by the induction of p53 and the consequent apoptosis at early stages (20).…”

“…Several factors, including the clinical characteristics, differentiate between BCCs and SCCs, being the latter more aggressive with increased metastatic properties. The major factor responsible for development of NMSC is UV radiation (1,2). However, whereas for BCC development the genetic hallmark is abrogation of the patched-sonic hedgehog pathway, little is known about the causal alterations of SCCs.…”

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

“…The apoptotic response has been extensively studied because elimination of DNA damaged KCs is an efficient and powerful protective mechanism for preventing development of skin cancer (Ziegler et al, 1994). While UV-light exposure triggers an assortment of cellular alterations involving multiple signaling pathways, dissection of the apoptotic response revealed it is principally mediated by mitochondrial dysfunction (Jackson et al, 2000;Nickoloff et al, 2002;Bowden, 2004).…”