IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR.
As an established mediator of inflammation, interleukin-6 (IL-6) is implicated to facilitate prostate cancer progression to androgen independence through transactivation of the androgen receptor. However, whether IL-6 has a causative role in de novo prostate tumorigenesis was never investigated. We now provide the first evidence that IL-6 can induce tumorigenic conversion and further progression to an invasive phenotype of non-tumorigenic benign prostate epithelial cells. Moreover, we find that paracrine IL-6 stimulates the autocrine IL-6 loop and autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer the tumorigenic property and also that activation of signal transducer and activator of transcription 3 (STAT3) is critical in these processes. Inhibition of STAT3 activation or IGF-IR signaling suppresses IL-6-mediated malignant conversion and the associated invasive phenotype. Inhibition of STAT3 activation suppresses IL-6-induced upregulation of IGF-IR and its ligands, namely IGF-I and IGF-II. These findings indicate that IL-6 signaling cooperates with IGF-IR signaling in the prostate microenvironment to promote prostate tumorigenesis and progression to aggressiveness. Our findings suggest that STAT3 and IGF-IR may represent potential effective targets for prevention or treatment of prostate cancer.
Department of Medicine, University of Washington, Seattle, WA 98104, USA.
A
A
Rojas
G
G
Liu
I
I
Coleman
P S
PS
Nelson
M
M
Zhang
R
R
Dash
P B
PB
Fisher
S R
SR
Plymate
J D
JD
Wu
D019898:Autocrine Communication; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D004847:Epithelial Cells; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D017526:Receptor, IGF Type 1
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