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Cited by 71Autophagy in Disease and TherapyPI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex Research

Impaired autophagy due to constitutive mTOR activation sensitizes TSC2-null cells to cell death under stress

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Ng, Shukie, Wu, You-Tong, Chen, Bo, Zhou, Jing, Shen, Han-Ming·2011·Autophagy
DOI 10.4161/auto.7.10.16681
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Abstract

It has been well documented that cells deficient in either TSC1 or TSC2 are highly sensitive to various cell death stimuli. In this study, we utilized the TSC2 (-/-) mouse embryonic fibroblasts (MEFs) to study the involvement of autophagy in the enhanced susceptibility of TSC2-null cells to cell death. We first confirmed that both TSC1-null and TSC2-null MEFs are more sensitive to apoptosis in response to amino acid starvation (EBSS) and hypoxia. Second, we found that both the basal and inducible autophagy in TSC2 (-/-) MEFs is impaired, mainly due to constitutive activation of mTORC1. Third, suppression of autophagy by chloroquine and Atg7 knockdown sensitizes TSC2 (+/+) cells, but not TSC2 (-/-) cells, to EBSS-induced cell death. Conversely, the inhibition of mTORC1 by raptor knockdown and rapamycin activates autophagy and subsequently rescues TSC2 (-/-) cells. Finally, in starved cells, nutrient supplementations (insulin-like growth factor-1 (IGF-1) and leucine) enhanced cell death in TSC2 (-/-) cells, but reduced cell death in TSC2 (+/+) cells. Taken together, these data indicate that constitutive activation of mTORC1 in TSC2 (-/-) cells leads to suppression of autophagy and enhanced susceptibility to stress-mediated cell death. Our findings thus provide new insights into the complex relationships among mTOR, autophagy and cell death, and support the possible autophagy-targeted intervention strategies for the treatment of TSC-related pathologies.

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Cited by

Sorted by citations

Authors
Ng, S., Wu, Y.-T., Chen, B., Zhou, J., & Shen, H.-M.
Affiliations
National University of Singapore (SG)
Corresponding author
Shen, Han-Ming
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2011-10
Volume
7
Issue
10
Pages
1173-1186
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.4161/auto.7.10.16681
OpenAlex
W2007448026
Cited by
71
References
0
Citations by year
2026: 1 · 2025: 5 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 4 · 2014: 8 · 2013: 5 · 2012: 11
FWCI
5.45
Type
journal article
Language
en
Open access
Locations
  • Autophagy (publishedVersion)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
Funders
Biomedical Research Council
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
Keywords
mTORC1, TSC2, TSC1, tuberous sclerosis complex, apoptosis, amino acid starvation, hypoxia, stress-induced cell death, raptors, rapamycin, ATG7, chloroquine, insulin-like growth factor I, leucine, mouse embryonic fibroblasts
MeSH terms
Autophagy-Related Protein 7, Mechanistic Target of Rapamycin Complex 1, Animals, Autophagy, Cell Line, Cell Survival, Chloroquine, Fibroblasts, Microtubule-Associated Proteins, Proteins, Time Factors, Signal Transduction, Cell Death, Transgenes, RNA, Small Interfering, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases

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