Survivin expression in tuberous sclerosis complex cells.
Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene disorder with mutations of TSC1/TSC2 genes. This leads to the development of hamartomas that most frequently affect central nervous system, kidney, and skin. Angiomyolipomas are abdominal masses made up of muscle vessels and adipose tissues that grow mostly in proximity to kidneys and liver. Bleeding and kidney failure are the major justification for surgery. This study shows that angiomyolipoma-derived human smooth muscle TSC2-/- cells express the apoptosis inhibitor protein survivin when exposed to IGF-1. Survivin expression is also triggered whenever culture conditions perturb normal TSC2-/- cell function, such as the omission of EGF from the growth medium, the supplementation of anti-EGFR, blockade of PI3K and ERK, or inhibition of mTOR. Interestingly, single or simultaneous inhibition of PI3K by LY294002 and ERK by PD98059 does not prevent IGF-1-mediated survivin expression. Apoptogenic Smac/DIABLO, which is constitutively expressed by TSC2-/- A+ cells, is down-regulated by IGF-1 even in the presence of LY294002 and PD98059. These cells release IGF-1 by means of a negative feedback-regulated mechanism that is overrun when they are exposed to antibodies to IGF-1R, which increases the released amount by more than 400%. The autocrine release of IGF-1 may therefore be a powerful mechanism of survival of the tightly packed cells in the thick-walled vessels of TSC angiomyolipoma and in lymphangioleiomyomatosis (LAM) nodules. Future experimental therapies for TSC and LAM may result from the targeted inhibition of survivin, which may enhance sensitivity to TSC2 therapy.
Carelli
Stephana
S
Laboratory of Pharmacology, Department of Medicine, Surgery and Dentistry, University of Milan, Polo H. San Paolo, Milano, Italy.
Lesma
Elena
E
Paratore
Simona
S
Grande
Vera
V
Zadra
Giorgia
G
Bosari
Silvano
S
Di Giulio
Anna Maria
AM
Gorio
Alfredo
A
D000328:Adult; D018207:Angiomyolipoma / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I