Insulin-like growth factor I suppresses bone morphogenetic protein signaling in prostate cancer cells by activating mTOR signaling
Authors: Kyung Song
Dorjee T N Shola
Reema S Wahdan-Alaswad
Tracy L Krebs
David Danielpour
Shigemi Matsuyama
Jose A Gomez
Journal: Cancer research (2010)
Discipline: CLINICAL MEDICINE
Keywords: Insulin-like growth factor; BMP4; prostate cancer; apoptosis; Smad-mediated gene expression
Affiliations: 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.

Abstract:  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. 

Retracted: Yes

PubPeer comments:
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 2020 retraction. https: cancerres.aacrjournals.org content 80 9 1902 This article (1) is being retracted at the request of the corresponding author. Errors were found in Figs. 1A, 3C, and 4D that diminish the reliability of this study. In Fig. 1A, the Western blot image for u03b2-actin was an erroneous duplication of the image for Smad2 in both the right and left panels. In addition, the original Western blot data for Smad3 and Smad 1 5 8 could not be identified. In Fig. 3C, the Western blot image for Smad1 5 8 on the left was found to be a duplication of Smad1 5 8 on the right; the original data do not specify which of the two figures it is associated with. In Fig. 4D, the Western blot image for P-Smad1 5 8 (Ab#2) on the right was found to be a different exposure of P-Smad1 5 8 (Ab#1) on the left. In addition, the original data for Smad 1 5 8 could not be identified. The authors apologize to the scientific community and deeply regret any inconveniences or challenges resulting from the publication and subsequent retraction of this article. A copy of this retraction notice was sent to the last known e-mail addresses for all seven authors. Five authors (K. Song, D.T.N. Shola, J.A. Gomez, S. Matsuyama, and D. Danielpour) agreed to the retraction; one author (R.S. Wahdan-Alaswad) did not agree to the retraction; and one author (T.L. Krebs) did not respond. Reference 1.u21b5Wahdan-Alaswad RS, Song K, Krebs TL, Shola DT, Gomez JA, Matsuyama S, et al. Insulin-like growth factor I suppresses bone morphogenetic protein signaling in prostate cancer cells by activating mTOR signaling. Cancer Res 2010;70:9106u201317. ,