title: Adiponectin pathway attenuates malignant mesothelioma cell growth.
abstract: Malignant mesothelioma (MM) is caused by exposure to asbestos. Because MM has a latency period, short survival time, and has a poor response to current therapeutic regimes, long-term preventive strategies are required to suppress the advance of pathological states after asbestos exposure. Accumulating evidence suggests that adiponectin plays a crucial role in the regulation of energy metabolism by increasing AMP-activated protein kinase (AMPK) activation. Several studies have indicated that the activation of AMPK decreases cyclooxygenase (COX)-2 expression. Because high COX-2 levels correlated with a worse prognosis and survival rate in MM, we examined whether the adiponectin pathway suppresses MM cell growth through the AMPK/COX-2 pathway. In vivo, dietary fish oil (a potential promoter of adiponectin) decreased the growth rate of MM, which was accompanied by an increase in adiponectin and phospho-AMPK levels, and a decrease in COX-2 level. In vitro, adiponectin significantly impaired the cell proliferation rate of MM cell lines. These effects partly involved induction of growth arrest and apoptosis to MM cells. MM cells expressed both adiponectin receptors 1 and 2 (AdipoR1 and -R2) at mRNA and proteins levels. These receptors were functional, because adiponectin activated AMPK. Adiponectin treatment also significantly down-regulated protein levels of COX-2 and its downstream prostaglandin E(2). Finally, inhibitory analysis of AdipoR1/R2 by small interfering RNA knockdown suggests that adiponectin enhances AMPK activity and impairs the cell proliferation rate of MM cells, mainly via AdipoR1. These findings suggest that the induction or supplementation of adiponectin is an important tactic for developing therapeutic strategies against MM.
authors.affiliation: Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
authors.forename: Kaijun
authors.initials: K
authors.lastname: Niu
authors.forename: Masanori
authors.initials: M
authors.lastname: Asada
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Okazaki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yamanda
authors.forename: Takae
authors.initials: T
authors.lastname: Ebihara
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.forename: Dongying
authors.initials: D
authors.lastname: Zhang
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nagatomi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kohzuki
authors.forename: Satoru
authors.initials: S
authors.lastname: Ebihara
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D052242:Adiponectin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004032:Diet; D005395:Fish Oils / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D011494:Protein Kinases / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C499918:ADIPOQ protein, human; C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D005395:Fish Oils; D054419:Receptors, Adiponectin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases