title: TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin.
abstract: Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin.
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Jose Felix
authors.initials: JF
authors.lastname: Moruno-Manchon
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Ndidi-Ese
authors.initials: NE
authors.lastname: Uzor
authors.affiliation: Department of Neuro-Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shelli R
authors.initials: SR
authors.lastname: Kesler
authors.affiliation: Department of Neuro-Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wefel
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Debra M
authors.initials: DM
authors.lastname: Townley
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNA, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Cancer Biology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Archana Sidalaghatta
authors.initials: AS
authors.lastname: Nagaraja
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNA, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Cancer Biology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNA, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Cancer Biology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNA, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Cancer Biology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Tsvetkov
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000502:physiology; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D066292:Lipid Droplets / Q000502:physiology; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009474:Neurons / Q000502:physiology*; D051381:Rats; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; C574124:TFEB protein, rat; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin
keywords: TFEB; autophagy; brain aging; chemotherapy; doxorubicin