title: YC-1 rescues cancer cachexia by affecting lipolysis and adipogenesis.
abstract: Loss of adipose tissue, primarily due to increased lipolysis but also to an impairment of adipogenesis, is a key feature of weight loss in cancer cachexia. Because of the myriad pathogenic signaling pathways essential for atrophy of adipose tissue, effective therapeutic agents for cachectic adipose loss are lacking and urgently needed. The authors evaluated the effects of YC-1 on adipogenesis of 3T3-L1 preadipocytes, TNF-α- and tumor-cell-induced lipolysis in 3T3-L1 adipocytes, and cachectic weight loss in colon-26 adenocarcinoma-bearing mice because YC-1 has been shown to possess versatile pharmacological actions, including anticancer activity. It was found that YC-1 promotes the differentiation of 3T3-L1 preadipocytes into adipocytes through activation of Akt and extracellular signal-regulated kinase (ERK) signaling pathways as well as activation of several adipogenic mediators, such as peroxisome proliferator-activated receptor γ (PPARγ), insulin receptor α (IRα), insulin receptor substrate-3 (IRS-3) and glucose transporter-4 (GLUT-4). In the in vitro lipolysis models, YC-1 attenuates TNF-α-induced lipolysis of adipocytes by antagonizing TNF-α-mediated activation of ERK and downregulation of perilipin (PLIN). It was also found that YC-1 inhibits colon-26 adenocarcinoma cell-induced lipolysis of 3T3-L1 adipocytes. Moreover, YC-1 effectively rescues cachectic weight loss in colon-26 adenocarcinoma-bearing mice by blocking lipolysis, involving insulin. Taken together the results show that YC-1 with its anticancer and anticachexia talents is highly worth developing as a novel agent for cancer therapy.
authors.affiliation: Center for Nanomedicine Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Tsai-Hua
authors.initials: TH
authors.lastname: Chung
authors.forename: Mark
authors.initials: M
authors.lastname: Yen-Ping Kuo
authors.forename: Jen-Kun
authors.initials: JK
authors.lastname: Chen
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Huang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D007191:Indazoles; D014409:Tumor Necrosis Factor-alpha; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole