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Survivin expression in tuberous sclerosis complex cells
Stephana Carelli1, Elena Lesma, Simona Paratore
1Laboratory of Pharmacology, Department of Medicine, Surgery and Dentistry, University of Milan, Polo H. San Paolo, Milano, Italy.
Molecular Medicine (Cambridge, Mass.)
|June 27, 2007
Summary
Tuberous Sclerosis Complex (TSC) cells lacking TSC2 produce survivin, an apoptosis inhibitor, when stimulated by IGF-1 or under stress. This suggests survivin inhibition could be a therapeutic strategy for TSC and LAM.
Area of Science:
- Oncology
- Cell Biology
- Genetics
Background:
- Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations in TSC1/TSC2 tumor suppressor genes.
- TSC leads to hamartoma formation, affecting organs like the brain, kidneys, and skin.
- Angiomyolipomas, common in TSC, are benign tumors of blood vessels and adipose tissue, often near the kidneys and liver, posing risks of bleeding and kidney failure.
Purpose of the Study:
- To investigate the role of Insulin-like Growth Factor 1 (IGF-1) in survivin expression in TSC2-deficient cells.
- To explore the signaling pathways involved in survivin regulation in the context of TSC.
- To identify potential therapeutic targets for TSC and Lymphangioleiomyomatosis (LAM).
Main Methods:
- Cultured human smooth muscle cells derived from angiomyolipomas with TSC2 deficiency (TSC2-/-).
- Stimulation with IGF-1 and various pathway inhibitors (anti-EGFR, PI3K, ERK, mTOR).
- Analysis of survivin and Smac/DIABLO protein expression and IGF-1 release.
Main Results:
- TSC2-/- cells express survivin upon IGF-1 exposure.
- Survivin expression is also induced by perturbations in culture conditions, including EGF omission and pathway inhibition.
- IGF-1 down-regulates the pro-apoptotic protein Smac/DIABLO.
- Cells exhibit a feedback loop for IGF-1 release, significantly increased by IGF-1 receptor blockade.
- Autocrine IGF-1 signaling appears crucial for cell survival in TSC angiomyolipomas and LAM.
Conclusions:
- IGF-1 signaling and cellular stress promote survivin expression in TSC2-deficient cells, contributing to cell survival.
- Targeting survivin may enhance the efficacy of therapies aimed at TSC2.
- Understanding these survival mechanisms could lead to novel therapeutic strategies for TSC and LAM.
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