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J. Biol. Chem., Vol. 279, Issue 20, 21154-21159, May 14, 2004

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Interleukin 6 Mediates the Lysophosphatidic Acid-regulated Cross-talk between Stromal and Epithelial Prostate Cancer Cells^*

Perumal Sivashanmugam, Linda Tang, and Yehia Daaka¶

From the Departments of Surgery and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

The interaction between stromal and epithelial cells is critical for the initiation and progression of prostate cancer, but the molecular determinants responsible for the cross-talk between these two cell types remain largely unknown. Here, we used a co-culture cell assay to identify messengers involved in the cross-talk between human prostate stromal PS30 and epithelial LNCaP cells. Stimulation with lysophosphatidic acid (LPA) activates the mitogenic ERK signaling pathway in PS30, but not LNCaP, cells. The co-culture of PS30 and LNCaP cells results in the activation of ERK in LNCaP cells and that is further increased in response to stimulation with LPA. Physiologic relevance of the interaction between PS30 and LNCaP cells is demonstrated using LNCaP xenograft tumor assays. Animals implanted with a mixture of both cell types develop larger tumors with higher frequency compared with those injected with LNCaP cells alone. Conditioned medium transfer experiments reveal the PS30-derived inducing factor is soluble and promotes mitogenic ERK and STAT3 signaling pathways in LNCaP cells. Protein analysis demonstrates that treatment of the PS30 cells with LPA induces synthesis of interleukin 6 (IL-6). Antibody neutralization experiments reveal that IL-6 is responsible for the LPA-induced mitogenic signaling and growth of the LNCaP cells. Our findings reveal that the LPA-regulated secretion of IL-6 is an important messenger linking stromal and epithelial prostate cells, which may be exploited for the effective treatment of patients with advanced prostate cancer.

Received for publication, December 16, 2003 , and in revised form, February 19, 2004.

^* This work was supported by Grants AG17952 and DK60917 from the National Institutes of Health (to Y. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Duke University Medical Center 2607, Durham, NC 27710. Tel.: 919-684-8440; Fax: 919-684-9990; E-mail: daaka001{at}mc.duke.edu.

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