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Carcinogenesis Advance Access published online on April 7, 2009
Carcinogenesis, 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,* and David K. Ornstein1,*

1 Department of Urology, University of California, Irvine, Orange, CA
2 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Corresponding author: Darren R. Tyson, Department of Cancer Biology, Vanderbilt University, 2220 Pierce Avenue, PRB 771, Nashville, TN 37232. Email: darren.tyson{at}vanderbilt.edu Phone: 615-936-1534 Fax: 615-936-1190

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 nontumorigenic 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.

Key Words: Annexin A1 • IL-6 • prostate carcinogenesis • 3D culture

* Sharing senior authorship

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


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