br Acknowledgements This work was
Acknowledgements This work was supported by grants from Agence Nationale de la Recherche (ANR CAPHE) and from Ligue contre le Cancer. We acknowledge the continuous support of CNRS and the University of Strasbourg. We thank the technical assistance of the “Plateforme de Chimie Intégrative de Strasbourg” (PCBIS) and the help of Dr. Clarisse Maechling for microcalorimetry experiments. All this work has been inspired from discussions with D. M. Watterson.
Introduction Arsenic compounds or arsenicals are well-known toxic and carcinogenic agents (IARC, 1980, Wang et al., 2002). The genotoxic and co-genotoxic effects of inorganic arsenicals are well documented in mammalian systems, both in vitro (Jha et al., 1992) and in vivo (Tice et al., 1997). A number of hypotheses have been formulated to explain the genotoxicity of arsenicals, and it appears that a variety of mechanisms may be involved in the toxicity of these compounds (Raisuddin and Jha, 2004). The toxic effects of arsenic that are of most concern to humans are those that occur from chronic, low-level exposure. Arsenic is primarily associated with various human malignancies, including skin and lung cancers. The Fenofibrate is also a target since it is the site where the arsenic compounds must accumulate for excretion. Autophagy is a process where cytoplasmic material, including organelles, is segregated into a double membrane-bound vesicle and then delivered to the lysosomal compartment for degradation (Eskelinen, 2005, Eskelinen et al., 2005). There are three major forms of autophagy, i.e. macro-autophagy, micro-autophagy and chaperone-mediated autophagy (Cuervo, 2004b). Two main functions have been proposed for the autophagic process. Firstly, autophagy is a short-term stress response in nutrient-limited conditions or amino-acid deficiency. It was coined to describe how a cell, facing starvation, degrades intracellular components to obtain nutrients for survival. Secondly, it is suggested that autophagy plays a role in type II, or autophagic, cell death (Gozuacik and Kimchi, 2004). The protein that is essential for autophagosome formation is Beclin-1, a 60-kDa coiled-coil protein encoded by beclin-1 gene. It binds to class III PI3K, which regulate autophagosome formation (Kihara et al., 2001). In the early stage of carcinogenesis, activation of autophagy may block tumor growth, while in the late stage; it favors survival of cells in low-vascularized tumors and removal of damaged intracellular macromolecules after anticancer treatments (Cuervo, 2004b). However, it has also been shown that the cellular autophagic capacity is highly increased in azaserine-induced premalignant atypical acinar nodule cells (Rez et al., 1999). Therefore, the role of autophagy in carcinogenesis is still uncertain. DAPK (Death Associated Protein Kinase) was first identified from a genetic screening for positive mediators of apoptotic stimuli, and the DAPK gene was located on chromosome 9q34.1 (Deiss et al., 1995, Feinstein et al., 1995). The DAPK family contains three closely related serine/threonine kinases, named DAPK, ZIPk and DRP-1, which display a high degree of homology in their catalytic domains. DAPK is a 160-kD Ca2+/calmodulin (CaM)-regulated Ser/Thr kinase that mediates cell death. The DAPK protein contains N-terminal kinase domain and the calmodulin binding region, following by eight ankyrin repeats. The cytoskeleton-associated region is on the middle part and the C-terminal of DAPK contains a conserved death of DAPK domain. DAPK acts as a tumor suppressor; it suppresses tumor growth and metastasis by increasing the occurrence of apoptosis in vivo (Inbal et al., 1997). It has been shown that hypermethylation in the promoter CpG region of DAPK gene with reduced DAPK protein expression was related to various human cancers, including lung, stomach, and bladder cancers (Chan et al., 2002, Kang et al., 2001, Kim et al., 2001).