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J. Biol. Chem., Vol. 278, Issue 43, 42660-42667, October 24, 2003

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Prostate Cancer Cell-Adipocyte Interaction

LEPTIN MEDIATES ANDROGEN-INDEPENDENT PROSTATE CANCER CELL PROLIFERATION THROUGH c-Jun NH₂-TERMINAL KINASE^*

Michiko Onuma, Jeffrey D. Bub, Thomas L. Rummel, and Yoshiki Iwamoto

From the Department of Urology, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH₂-terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgen-independent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.

Received for publication, May 13, 2003 , and in revised form, July 22, 2003.

^* 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.

Supported by a fellowship from the Northwestern Mutual Life Foundation.

To whom correspondence should be addressed. Tel.: 414-456-4678; Fax: 414-456-6516; E-mail: yiwamoto{at}mcw.edu.

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