title: PKA/AMPK signaling in relation to adiponectin's antiproliferative effect on multiple myeloma cells.
abstract: Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin's ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.
authors.affiliation: Division of Hematopathology, Department of Pathology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Medina
authors.affiliation: Division of Hematopathology, Department of Pathology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Oberheu
authors.affiliation: Division of Hematopathology, Department of Pathology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Polusani
authors.affiliation: Division of Hematopathology, Department of Pathology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ortega
authors.affiliation: Division of Hematopathology, Department of Pathology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: G V N
authors.initials: GV
authors.lastname: Velagaleti
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: B O
authors.initials: BO
authors.lastname: Oyajobi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism; D052242:Adiponectin / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D018450:Disease Progression; D005227:Fatty Acids / Q000737:chemistry; D005663:Furans / Q000737:chemistry; D006801:Humans; D050155:Lipogenesis; D008661:Metabolism, Inborn Errors / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054392:Adipokines; D052242:Adiponectin; D005227:Fatty Acids; D005663:Furans; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase