title: Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent.
abstract: Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome characterized by benign tumors in multiple organs, including the brain and kidney. TSC-associated tumors exhibit hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), a direct inhibitor of autophagy. Autophagy can either promote or inhibit tumorigenesis, depending on the cellular context. The role of autophagy in the pathogenesis and treatment of the multisystem manifestations of TSC is unknown. We found that the combination of mTORC1 and autophagy inhibition was more effective than either treatment alone in inhibiting the survival of tuberin (TSC2)-null cells, growth of TSC2-null xenograft tumors, and development of spontaneous renal tumors in Tsc2(+/-) mice. Down-regulation of Atg5 induced extensive central necrosis in TSC2-null xenograft tumors, and loss of one allele of Beclin1 almost completely blocked macroscopic renal tumor formation in Tsc2(+/-) mice. Surprisingly, given the finding that lowering autophagy blocks TSC tumorigenesis, genetic down-regulation of p62/sequestosome 1 (SQSTM1), the autophagy substrate that accumulates in TSC tumors as a consequence of low autophagy levels, strongly inhibited the growth of TSC2-null xenograft tumors. These data demonstrate that autophagy is a critical component of TSC tumorigenesis, suggest that mTORC1 inhibitors may have autophagy-dependent prosurvival effects in TSC, and reveal two distinct therapeutic targets for TSC: autophagy and the autophagy target p62/SQSTM1.
authors: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Andrey
authors: A
authors: Parkhitko
authors: Faina
authors: F
authors: Myachina
authors: Tasha A
authors: TA
authors: Morrison
authors: Khadijah M
authors: KM
authors: Hindi
authors: Neil
authors: N
authors: Auricchio
authors: Magdalena
authors: M
authors: Karbowniczek
authors: J Julia
authors: JJ
authors: Wu
authors: Toren
authors: T
authors: Finkel
authors: David J
authors: DJ
authors: Kwiatkowski
authors: Jane J
authors: JJ
authors: Yu
authors: Elizabeth Petri
authors: EP
authors: Henske
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D016158:Genes, p53; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D046912:Multiprotein Complexes; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases