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Research Paper|Volume 8, Issue 12|pp 3507—3519

TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin

Jose Felix Moruno-Manchon1, Ndidi-Ese Uzor1,2, Shelli R. Kesler3, Jeffrey S. Wefel3, Debra M. Townley4, Archana Sidalaghatta Nagaraja5,6,7, Sunila Pradeep5,6,7, Lingegowda S. Mangala5,6,7, Anil K. Sood5,6,7, Andrey S. Tsvetkov1,2
  • 1Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
  • 2The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
  • 3Department of Neuro-Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
  • 4Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
  • 5Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
  • 6Center for RNA Interference and Non-Coding RNA, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
  • 7Department of Cancer Biology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
Received: September 5, 2016Accepted: December 12, 2016Published: December 16, 2016

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.