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Research Article

Capsaicin, a Component of Red Peppers, Inhibits the Growth of Androgen-Independent, p53 Mutant Prostate Cancer Cells

Akio Mori,1 So¨ren Lehmann,1 James O’Kelly,1 Takashi Kumagai,1 Julian C. Desmond,1 Milena Pervan,2 William H. McBride,2 Masahiro Kizaki,3 and H. Phillip Koeffler1

1Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine; 2Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and 3Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Abstract

Capsaicin is the major pungent ingredient in red peppers. Here, we report that it has a profound antiproliferative effect on prostate cancer cells, inducing the apoptosis of both androgen receptor (AR)-positive (LNCaP) and -negative (PC-3, DU-145) prostate cancer cell lines associated with an increase of p53, p21, and Bax. Capsaicin down-regulated the expression of not only prostate-specific antigen (PSA) but also AR. Promoter assays showed that capsaicin inhibited the ability of dihydro- testosterone to activate the PSA promoter/enhancer even in the presence of exogenous AR in LNCaP cells, suggesting that capsaicin inhibited the transcription of PSA not only via down- regulation of expression of AR, but also by a direct inhibitory effect on PSA transcription. Capsaicin inhibited NF-K activa- tion by preventing its nuclear migration. In further studies, capsaicin inhibited tumor necrosis factor-A–stimulated deg- radation of IKBA in PC-3 cells, which was associated with the inhibition of proteasome activity. Taken together, capsaicin inhibits proteasome activity which suppressed the degradation of IKBA, preventing the activation of NF-KB. Capsaicin, when given orally, significantly slowed the growth of PC-3 prostate cancer xenografts as measured by size [75 F 35 versus 336 F 123 mm3 (FSD); P = 0.017] and weight [203 F 41 versus 373 F 52 mg (FSD); P = 0.0006; capsaicin-treated versus vehicle- treated mice, respectively]. In summary, our data suggests that capsaicin, or a related analogue, may have a role in the management of prostate cancer. (Cancer Res 2006; 66(6): 3222-9)

Introduction

Prostate cancer is an increasingly prevalent health problem in the U.S., with >230,000 new cases and 29,000 deaths occurring as a result of the disease every year, thereby, constituting the most common male malignancy. Despite the prevalence of the disease, no successful, long-term therapies exist once the cancer has relapsed. The limited therapeutic options provide a strong stimulus for developing new therapeutic approaches.

Capsaicin, a homovanillic acid derivative (8-methyl-N-vanillyl-6- nonenamide), is an active component of the red pepper, genus Capsicum, used for many years in food additives and drugs (1). Topically, capsaicin has therapeutic value in a variety of neuropathic pain conditions including rheumatoid arthritis, cluster

headaches, herpes zoster, and vasomotor rhinitis (2–5). Further- more, capsaicin decreases the growth of human leukemic cells (6–8), gastric (9), and hepatic carcinoma cells in vitro (10). However, the mechanism of capsaicin-induced growth inhibition remains unclear, and the effect of capsaicin on the growth of human prostate cancer cells has not been studied.

Analysis of androgen-responsiveness of prostate cancer cells often uses prostate-specific antigen (PSA) as a surrogate marker. The 5Vupstream promoter and enhancer region of the PSA gene has several androgen response (AR) elements (ARE), and the expression of PSA is regulated by binding of the liganded AR to these AREs (11–13). A recent study revealed that the nuclear transcription factor nB (NF-nB) is constitutively activated in the androgen- independent prostate cancer cell lines PC-3 and DU-145, but not in the androgen-responsive LNCaP human prostate cancer cells (13). NF-nB is a generic term for a dimeric transcription factor formed by heterodimerization or homodimerization of a number of Rel family members (14). These transcription factors are activated by a wide range of stimuli, including DNA damage, free radicals, and cytokines, such as tumor necrosis factor-a (TNF-a; ref. 15). In unstimulated cells, NF-nB is maintained in an inactive state in the cytoplasm by complexing with members of the InB inhibitory protein family, including InBa and InBh (16). The interaction between NF-nB and InBa prevents NF-nB’s nuclear localization and DNA binding activity (15, 16). With activation, InBa kinase (IKK) stimulates the ubiquitination of InBa, resulting in its degradation by the 26S proteasome complex (17). NF-nB is then free to translocate to the nucleus and act as a transcription factor for a variety of genes, including cytokines, cell cycle regulatory proteins as well as antiapoptotic proteins (15, 16, 18). An earlier study noted that capsaicin may exert its anti-growth effects in human myeloid cells through inhibition of the activity of the transcription factor NF-nB by blocking the degradation of InBa, thereby inhibiting the translocation of the p65 subunit of NF-nB to the nucleus (19).

In the present studies, we show that capsaicin has a profound inhibiting effect on the growth of prostate cancer cells in vitro and in vivo, inducing the apoptosis of both AR-positive and AR-negative prostate cancer cell lines. We also showed that capsaicin profoundly decreased the transcription of AR target genes.

Materials and Methods

Note: A. Mori and S. Lehmann contributed equally to the manuscript. Requests for reprints: So¨ren Lehmann, Cedars-Sinai Medical Center/University of California at Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7758; Fax: 310-423-0225; E-mail: LehmannS@cshs.org. I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-0087

Cells and compounds. LNCaP, PC-3, and DU-145 cells (American Type Culture Collection, Manassas, VA) were maintained at 37jC in 5% CO2 in RPMI 1640 (Life Technologies, Rockville, MD) with 10% fetal bovine serum (FBS; Omega, Tarzana, CA). Capsaicin and capsazepine (Sigma Chemical Co., St. Louis, MO) were dissolved in 100% ethanol or 100% methanol, respectively. Ruthenium red (Calbiochem, La Jolla, CA), SB366791, resin- iferatoxin (Alexis Biochemicals, San Diego, CA), and dihydrotestosterone (Sigma Chemical) were dissolved in 100% ethanol. TNF-a (Sigma Chemical)

Cancer Res 2006; 66: (6). March 15, 2006

3222

www.aacrjournals.org

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