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

Andrey Parkhitko1, Faina Myachina, Tasha A Morrison

  • 1Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 13, 2011
PubMed

Insights

Autophagy inhibition significantly hinders tuberous sclerosis complex (TSC) tumor growth. Targeting autophagy or its substrate p62/SQSTM1 offers novel therapeutic strategies for TSC.

Area of Science:

  • Oncology
  • Cell Biology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) is a genetic disorder causing benign tumors due to mutations in TSC1 or TSC2 genes.
  • TSC tumors exhibit hyperactivated mTORC1 signaling, a pathway that inhibits autophagy, a cellular degradation process.
  • The precise role of autophagy in TSC pathogenesis and its potential as a therapeutic target remain unclear.

Purpose of the Study:

  • To investigate the role of autophagy in the development and progression of TSC.
  • To evaluate the efficacy of combined mTORC1 and autophagy inhibition as a therapeutic strategy for TSC.
  • To identify novel therapeutic targets within the autophagy pathway for TSC treatment.

Main Methods:

  • Utilized TSC2-null cells and Tsc2(+/-) mice models to study tumor development.
  • Assessed the effects of inhibiting mTORC1 and autophagy, individually and in combination.
  • Examined the impact of down-regulating autophagy-related genes (Atg5, Beclin1) and the autophagy substrate p62/SQSTM1.

Main Results:

  • Combined mTORC1 and autophagy inhibition proved more effective than single-agent treatment in reducing tumor cell survival and growth.
  • Down-regulation of Atg5 led to central necrosis in xenograft tumors, while Beclin1 heterozygosity significantly blocked renal tumor formation.
  • Unexpectedly, genetic down-regulation of p62/SQSTM1, an autophagy substrate, strongly inhibited tumor growth.

Conclusions:

  • Autophagy is a critical driver of tumorigenesis in TSC.
  • mTORC1 inhibitors may exert prosurvival effects in TSC through autophagy-dependent mechanisms.
  • Autophagy and its target p62/SQSTM1 represent promising, distinct therapeutic targets for TSC.

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