title: Critical role of a survivin/TGF-β/mTORC1 axis in IGF-I-mediated growth of prostate epithelial cells.
abstract: Survivin is a unique member of the inhibitor of apoptosis (IAP) proteins that is overexpressed in numerous cancers through poorly defined mechanisms. One such mechanism may be through constitutive activation of the insulin-like growth factor-I (IGF-I) signaling pathway, implicated in the development and progression of prostate cancer. Using the pre-neoplastic NRP-152 rat prostate cell line as a model, we showed that IGF-I induces Survivin expression, and that silencing Survivin by lentiviral-mediated small hairpin RNA (shRNA) represses IGF-I-stimulated cell growth, implicating Survivin as a mediator of this growth response. Moreover, our data support that the induction of Survivin by IGF-I occurs through a transcriptional mechanism that is mediated in part by the PI3K/Akt/mTORC1 pathway. Use of various Survivin promoter-luciferase constructs revealed that the CDE and CHR response elements in the proximal region of the Survivin promoter are involved in this IGF-I response. Transforming growth factor (TGF-β) signaling antagonists similarly activated the Surivin promoter and rendered cells refractory to further promoter activation by IGF-I. IGF-I suppressed levels of phospho-Smads 2 and 3 with kinetics similar to that of Survivin induction. Suppression of TGF-β signaling, either by TGF-β receptor kinase inhibitors or by silencing Smads 2 and 3, induced Survivin expression and promoted cell growth similar to that induced by IGF-I. TGF-β receptor antagonists also rescued cells from down-regulation of Survivin expression and growth suppression by pharmacological inhibitors of PI3K, Akt, MEK and mTOR. Sh-RNA gene silencing studies suggest that mTORC1 induces while mTORC2 represses the expression of Survivin by IGF-I. Taken together, these results suggest that IGF-I signaling through a PI3K/Akt/mTORC1 mechanism elevates expression of Survivin and promotes growth of prostate epithelial cells by suppressing Smad-dependent autocrine TGF-β signaling.
authors: Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Kyung
authors: K
authors: Song
authors: Eswar
authors: E
authors: Shankar
authors: Jiayi
authors: J
authors: Yang
authors: Kara L
authors: KL
authors: Bane
authors: Reema
authors: R
authors: Wahdan-Alaswad
authors: David
authors: D
authors: Danielpour
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D020935:MAP Kinase Signaling System; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000166:cytology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D007334:Insulin-Like Growth Factor I; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein; D051785:Smad Proteins; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; C516989:Birc5 protein, rat; C084339:LR(3)IGF-I; C508962:Tgfb1 protein, rat
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