p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis.

Titlep62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis.
Publication TypeJournal Article
Year of Publication2017
AuthorsLam HC, Baglini CV, Lope ALlorente, Parkhitko AA, Liu H-J, Alesi N, Malinowska IA, Ebrahimi-Fakhari D, Saffari A, Yu JJ, Pereira A, Khabibullin D, Ogorek B, Nijmeh J, Kavanagh T, Handen A, Chan SY, Asara JM, Oldham WM, Diaz-Meco MT, Moscat J, Sahin M, Priolo C, Henske EP
JournalCancer Res
Volume77
Issue12
Pagination3255-3267
Date Published2017 06 15
ISSN1538-7445
KeywordsAnimals, Carcinogenesis, Disease Models, Animal, Fluorescent Antibody Technique, Glutathione, Immunohistochemistry, Kidney Neoplasms, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Mitochondria, Multiprotein Complexes, Sequestosome-1 Protein, TOR Serine-Threonine Kinases, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins
Abstract

p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2 and Tsc2f/f Ksp-CreERT2 mice crossed to p62 mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH). p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells. We also observed p62-dependent changes in Gcl, Gsr, Nqo1, and Srxn1, which were decreased by p62 attenuation and implicated in GSH production and utilization. p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial reactive oxygen species and mitophagy marker PINK1. These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells. Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of GSH biosynthesis by buthionine sulfoximine. Our findings show how p62 helps maintain intracellular pools of GSH needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors. .

DOI10.1158/0008-5472.CAN-16-2458
Alternate JournalCancer Res
PubMed ID28512249
PubMed Central IDPMC5485875
Grant ListR01 DK096556 / DK / NIDDK NIH HHS / United States
K08 HL128802 / HL / NHLBI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
R01 DK098331 / DK / NIDDK NIH HHS / United States
R01 HL122596 / HL / NHLBI NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
R01 HL098216 / HL / NHLBI NIH HHS / United States
R01 HL124021 / HL / NHLBI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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