Cachexia is a multifactorial wasting syndrome most common in patients with cancer that is characterized by the uncontrolled loss of adipose and muscle mass. We show that the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (Atgl) or hormone-sensitive lipase (Hsl) ameliorates certain features of cancer-associated cachexia (CAC). In wild-type C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue (WAT), and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased WAT lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected although to a lesser degree. Thus, functional lipolysis is essential in the pathogenesis of CAC. Pharmacological inhibition of metabolic lipases may help prevent cachexia.

Comparative gene identification-58 (CGI-58), also designated as ␣/␤-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58 ؊/؊ ) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58 ؊/؊ mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGLindependent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58.Fatty acids (FA) 3 are major energy substrates and essential components of membrane lipids as well as of numerous bioactive lipid species. Because excessive cellular concentrations of nonesterified FA are toxic, eukaryotic cells detoxify them by esterification to triacylglycerols (TG), which are subsequently stored in cellular lipid droplets (LD). Adipose tissue is the major storage organ for TG. However, some LD are found in essentially all cell types and tissues. Depending on the nutritional status and the energy demand of an organism, TG are synthesized (lipogenesis) or catabolized (lipolysis). Defects in the control of the finely regulated balance between lipogenesis and lipolysis result in the development of metabolic disorders such as obesity, type II diabetes, lipodystrophy, and neutral lipid storage disease (NLSD) (1-6).Hydrolysis of TG is mediated by the enzymatic activity of adipose triglyceride lipase (ATGL) (7-9) and hormone-sensitive lipase (10, 11). Whereas hormone-sensitive lipase-deficient mice exhibit a relatively benign phenotype (12, 13), mice lacking ATGL massively accumulate TG in multiple tissues, exhibit a severe defect in energy metabolism, and die prematurely due to cardiac dysfunction (14). Similarly, humans with mutations in the ATGL gene lacking normal enzyme function develop NLSD associated with skeletal and cardiac myopathy (15). In severe cases, cardiomyopathy necessitates heart transplantation (16).Studies in this laboratory and by others demonstrated that both human and murine ATGL are stimulated by a protein designated as CGI-58 (comparative gene identification-58) (17, 18) or ABHD5 (␣/␤-hydrolase domain...

Acquired drug resistance constitutes a major challenge for effective cancer therapies with melanoma being no exception. The dynamics leading to permanent resistance are poorly understood but are important to design better treatments. Here we show that drug exposure, hypoxia or nutrient starvation leads to an early innate cell response in melanoma cells resulting in multidrug resistance, termed induced drug-tolerant cells (IDTCs). Transition into the IDTC state seems to be an inherent stress reaction for survival toward unfavorable environmental conditions or drug exposure. The response comprises chromatin remodeling, activation of signaling cascades and markers implicated in cancer stemness with higher angiogenic potential and tumorigenicity. These changes are characterized by a common increase in CD271 expression concomitantly with loss of differentiation markers such as melan-A and tyrosinase, enhanced aldehyde dehydrogenase (ALDH) activity and upregulation of histone demethylases. Accordingly, IDTCs show a loss of H3K4me3, H3K27me3 and gain of H3K9me3 suggesting activation and repression of differential genes. Drug holidays at the IDTC state allow for reversion into parental cells re-sensitizing them to the drug they were primarily exposed to. However, upon continuous drug exposure IDTCs eventually transform into permanent and irreversible drug-resistant cells. Knockdown of CD271 or KDM5B decreases transition into the IDTC state substantially but does not prevent it. Targeting IDTCs would be crucial for sustainable disease management and prevention of acquired drug resistance.

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