Tuberous sclerosis complex and autophagy

Tuberous sclerosis complex (TSC) is a multi-system disorder caused by mutations in the TSC1 or TSC2 genes. As illustrated in the signalling diagram on, TSC1/2 plays an important role in regulating the mammalian target of rapamycin complex 1 (mTORC1), which is involved in a number of cellular functions including autophagy. Autophagy involves the degradation and recycling of a cell’s components and normally occurs during periods of cellular bioenergetic stress. However, it can also be involved in the development of disease. This last point is highlighted in a recent study by Parkhitko et al. (2011), in which autophagy and the autophagy substrate Sequestosome-1 (p62/SQSTM1) appear to be involved in TSC-associated tumourigenesis.

In this study, TSC2-null mouse embryonic fibroblasts (MEFs) were seen to have lower levels of autophagy, as demonstrated by reduced levels of LC3-II, increased levels of p62/SQSTM1, and fewer and smaller autophagosomes when compared to TSC2-positive controls. When treating these TSC2-null MEFs with the mTORC1 inhibitor rapamycin, the opposite was evident, with more LC3-II and less p62/SQSTM1 present, confirming that autophagy is regulated by mTORC1.

Chloroquine also affects autophagy by inhibiting lysosome-autophagosome fusion, and it was shown that combining chloroquine with rapamycin reduced mitochondrial respiration and ATP levels in TSC2-null cells more effectively than either drug alone. Moreover, cell death was greatly increased in TSC2-null ELT3 cells using both drugs together under nutrient-restricted conditions. In vivo experiments also showed that treatment with rapamycin and chloroquine reduced the size of TSC2-null MEF xenograft tumours more significantly than rapamycin alone. In addition, Parkhitko et al. examined the effect of the two drugs on spontaneous renal tumourigenesis in TSC2 heterozygote mice, and saw that the two drugs in combination led to fewer and smaller macroscopic renal lesions than either alone.

Finally, the authors noted that human TSC-associated tumours had significantly higher levels of p62/SQSTM1 compared to adjacent normal tissue. p62/SQSTM1 is thought to promote tumourigenesis (Mathew et al., 2009), but shRNA knockdown of p62/SQSTM1 had no effect on the growth and survival of TSC2-null MEFs in vitro. In contrast, p62/SQSTM1 shRNA knockdown delayed both tumour incidence and growth in TSC2-null MEF xenograft experiments, indicating that p62/SQSTM1 is required for TSC2-null cell tumour formation in vivo.

In summary, this study shows that autophagy is potentially involved in TSC-associated tumourigenesis. Given the clinical similarities between TSC and BHD syndrome (which have been discussed in a previous blog), could autophagy play a role in BHD-associated tumourigenesis and be a novel therapeutic target? Experiments involving rapamycin and chloroquine could shed more light on this issue.


  • Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009 Jun 12;137(6):1062-75. Erratum in: Cell. 2011 Apr 15;145(2):322.
  • Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ, Henske EP. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A. 2011 Jul 26; 108(30):12455-60. – the primary online resource for anyone interested in BHD Syndrome.


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