Insulin-like growth factor I suppresses bone morphogenetic protein signaling in prostate cancer cells by activating mTOR signaling.
Insulin-like growth factor (IGF) I and bone morphogenetic proteins (BMP) are critical regulators of prostate tumor cell growth. In this report, we offer evidence that a critical support of IGF-I in prostate cancer is mediated by its ability to suppress BMP4-induced apoptosis and Smad-mediated gene expression. Suppression of BMP4 signaling by IGF-I was reversed by chemical inhibitors of phosphoinositide 3-kinase (PI3K), Akt, or mTOR; by enforced expression of wild-type PTEN or dominant-negative PI3K; or by small hairpin RNA-mediated silencing of mTORC1/2 subunits Raptor or Rictor. Similarly, IGF-I suppressed BMP4-induced transcription of the Id1, Id2, and Id3 genes that are crucially involved in prostate tumor progression through PI3K-dependent and mTORC1/2-dependent mechanisms. Immunohistochemical analysis of non-malignant and malignant prostate tissues offered in vivo support for our model that IGF-I-mediated activation of mTOR suppresses phosphorylation of the BMP-activated Smad transcription factors. Our results offer the first evidence that IGF-I signaling through mTORC1/2 is a key homeostatic regulator of BMP4 function in prostate epithelial cells, acting at two levels to repress both the proapoptotic and pro-oncogenic signals of BMP-activated Smads. We suggest that deregulation of this homeostatic control may be pivotal to the development and progression of prostate cancer, providing important implications and new potential targets for the therapeutic intervention of this malignancy.
Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Department of Pharmacology, Case Western Reserve University, and Department of Urology, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Reema S
RS
Wahdan-Alaswad
Kyung
K
Song
Tracy L
TL
Krebs
Dorjee T N
DT
Shola
Jose A
JA
Gomez
Shigemi
S
Matsuyama
David
D
Danielpour
D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D055415:Bone Morphogenetic Protein 4; D051798:Inhibitor of Differentiation Protein 1; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D058570:TOR Serine-Threonine Kinases