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Carcinogenesis Advance Access originally published online on April 7, 2009
Carcinogenesis 2009 30(7):1082-1088; doi:10.1093/carcin/bgp078
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Loss of annexin A1 disrupts normal prostate glandular structure by inducing autocrine IL-6 signaling

Junichi Inokuchi1,2, Alice Lau1, Darren R. Tyson1,*,{dagger} and David K. Ornstein1,{dagger}

1 Department of Urology, University of California, Irvine, Orange, CA 92868, USA
2 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan

* To whom correspondence should be addressed. Department of Cancer Biology, Vanderbilt University, 2220 Pierce Avenue, PRB 771, Nashville, TN 37232, USA. Tel: +1 615 936 1534; Fax: +1 615 936 1190; Email: darren.tyson{at}vanderbilt.edu

Annexin A1 (ANXA1) expression is commonly reduced in premalignant lesions and prostate cancer, but a causal relationship of ANAX1 loss with carcinogenesis has not been established. ANXA1 levels have been shown to inversely correlate with interleukin 6 (IL-6) expression in other cell types and IL-6 has been suggested to enhance prostate cancer initiation and promotion. To investigate whether loss of ANXA1 may contribute to prostate carcinogenesis, ANXA1 expression was reduced using RNA interference in non-tumorigenic human prostatic epithelial cells (RWPE-1/rA1). No effect on morphology, apoptosis, migration or anchorage-dependent or -independent growth was detected. However, IL-6 mRNA and secreted protein levels were elevated in RWPE-1/rA1 cells. In addition, re-expression of ANXA1 in these cells suppressed IL-6 secretion, and altering ANXA1 levels in prostate cancer cells had similar effects on IL-6. The effects of ANXA1 loss and increased IL-6 expression on prostate epithelium were examined using an assay of acinar morphogenesis in vitro. Acini formed by RWPE-1/rA1 cells had delayed luminal clearing and larger mean diameters than control cells. The RWPE-1/rA1 phenotype was recapitulated by treating control cells with recombinant IL-6 and was reversed in RWPE-1/rA1 cells by blocking IL-6 bioactivity. Taken together, these data support a direct role for decreased ANXA1 expression in prostate carcinogenesis and enhancing tumor aggressiveness via the upregulation of IL-6 expression and activity.

Abbreviations: ANXA1, annexin A1; EGF, epidermal growth factor; IL-6, interleukin 6; K-SFM, keratinocyte serum-free medium containing 5 ng/ml EGF and 25 mg/ml bovine pituitary extract and 1% penicillin/streptomycin solution (P/S); NC, non-silencing control; PCR, polymerase chain reaction; P/S, penicillin/streptomycin solution; shRNA, short hairpin RNA; STAT3, signal transducer and activator of transcription 3; TNF-{alpha}, tumor necrosis factor-{alpha}

{dagger} Sharing senior authorship.

Received December 8, 2008; revised March 20, 2009; accepted April 1, 2009.


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