title: The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration.
abstract: Despite the success of antiretroviral therapies to control systemic HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HANDs) has not decreased among aging patients with HIV. Autophagy pathway alterations, triggered by HIV-1 proteins including gp120, Tat, and Nef, might contribute to the neurodegenerative process in aging patients with HAND. Although no treatments are currently available to manage HAND, we have previously shown that sunitinib, an anticancer drug that blocks receptor tyrosine-kinase and cyclin kinase pathways, might be of interest. Studies in cancer models suggest that sunitinib might also modulate autophagy, which is dysregulated in our models of Tat-induced neurotoxicity. We evaluated the efficacy of sunitinib to promote autophagy in the CNS and ameliorate neurodegeneration using LC3-GFP-expressing neuronal cells challenged with low concentrations of Tat and using inducible Tat transgenic mice. In neuronal cultures challenged with low levels of Tat, sunitinib increased markers of autophagy such as LC3-II and reduced p62 accumulation in a dose-dependent manner. In vivo, sunitinib treatment restored LC3-II, p62, and endophilin B1 (EndoB1) levels in doxycycline-induced Tat transgenic mice. Moreover, in these animals, sunitinib reduced the hyperactivation of CDK5, tau hyperphosphorylation, and p35 cleavage to p25. Restoration of CDK5 and autophagy were associated with reduced neurodegeneration and behavioral alterations. Alterations in autophagy in the Tat tg mice were associated with reduced levels of a CDK5 substrate, EndoB1, and levels of total EndoB1 were normalized by sunitinib treatment. We conclude that sunitinib might ameliorate Tat-mediated autophagy alterations and may decrease neurodegeneration in aging patients with HAND.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Jerel A
authors.initials: JA
authors.lastname: Fields
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Metcalf
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Cassia
authors.initials: C
authors.lastname: Overk
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Jazmin
authors.initials: J
authors.lastname: Florio
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: He
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, 92093-0624, USA. emasliah@ucsd.edu.|Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0624, USA. emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D060825:Cognitive Dysfunction / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000821:virology; D011758:Pyrroles / Q000494:pharmacology*; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077210:Sunitinib; D019076:Transgenes; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011758:Pyrroles; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D054322:tat Gene Products, Human Immunodeficiency Virus; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D000077210:Sunitinib
keywords: Autophagy; HIV-1; In vivo; Sunitinib