TY - JOUR
T1 - TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin
AU - Moruno Manchon, Jose Felix
AU - Uzor, Ndidi Ese
AU - Kesler, Shelli R.
AU - Wefel, Jeffrey S.
AU - Townley, Debra M.
AU - Nagaraja, Archana Sidalaghatta
AU - Pradeep, Sunila
AU - Mangala, Lingegowda S.
AU - Sood, Anil K.
AU - Tsvetkov, Andrey S.
N1 - Funding Information:
This work was supported by the University of Texas, McGovern Medical School at Houston, the Department of Neurobiology and Anatomy. This project was also supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from the NIH (HD007495, DK56338, CA109298, and CA125123), the Dan L. Duncan Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics, the Blanton-Davis Ovarian Cancer Research Program, and The Frank McGraw Memorial Chair in Cancer Research, the American Cancer Society Research Professor Award, and a grant from the National Institutes of Health (1R01NR014195 to JSW/SRK).
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Autophagy
KW - Brain aging
KW - Chemotherapy
KW - Doxorubicin
KW - TFEB
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U2 - 10.18632/aging.101144
DO - 10.18632/aging.101144
M3 - Article
C2 - 27992857
AN - SCOPUS:85010589813
SN - 1945-4589
VL - 8
SP - 3507
EP - 3519
JO - Aging
JF - Aging
IS - 12
ER -