Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent

Andrey Parkhitko, Faina Myachina, Tasha A. Morrison, Khadijah M. Hindi, Neil Auricchio, Magdalena Karbowniczek, J. Julia Wu, Toren Finkel, David J. Kwiatkowski, Jane J. Yu, Elizabeth Petri Henske

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)12455-12460
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number30
DOIs
StatePublished - Jul 26 2011
Externally publishedYes

Keywords

  • Cell survival
  • Chloroquine
  • Metabolism
  • Therapy

ASJC Scopus subject areas

  • General

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