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Galiellalactone is a novel therapeutic candidate against hormone‐refractory prostate cancer expressing activated Stat3
Author(s) -
Hellsten Rebecka,
Johansson Martin,
Dahlman Anna,
Dizeyi Nishtman,
Sterner Olov,
Bjartell Anders
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20699
Subject(s) - du145 , lncap , stat3 , cancer research , apoptosis , biology , microbiology and biotechnology , cell growth , cyclin d1 , prostate cancer , stat protein , chemistry , cell cycle , cancer , biochemistry , genetics
BACKGROUND Signal transducer and activator of transcription 3 (Stat3) is constitutively active (phosphorylated) in several forms of cancer, including prostate cancer (PCa). Stat3 signaling may be an interesting target for cancer therapy since inhibition of this pathway mediates growth inhibition and apoptosis of these cells. In this study we investigated the in vitro and in vivo effects of the fungal metabolite galiellalactone, a direct inhibitor of Stat3, on PCa cells. METHODS The human PCa cell lines DU145, PC‐3, and LNCaP were used. Nude mice with subcutaneous PCa cell xenografts were subjected to daily intraperitoneal injections of galiellalactone for 3 weeks. The effect of galiellalactone on the induction of apoptosis of cultured PCa cells was investigated by Western blot analysis, immunocytochemistry, and annexin V staining. Effects of galiellalactone on Stat3 signaling were investigated by a luciferase reporter gene assay. Expression of Stat3 associated proteins and mRNA was investigated by Western blot and real‐time quantitative PCR analysis. RESULTS Galiellalactone induced apoptosis of p‐Stat3 positive PCa cells (androgen‐insensitive DU145 and PC‐3) but not in cells lacking p‐Stat3 (androgen‐sensitive LNCaP). Galiellalactone inhibited Stat3‐mediated luciferase activity (IC 50 ∼ 5 µM) and reduced the expression of Bcl‐2, Bcl‐x L , c‐myc, and cyclin D1. Furthermore, galiellalactone significantly suppressed DU145 xenograft growth in vivo (42% growth reduction; P < 0.002) and reduced the relative mRNA expression of Bcl‐x L and Mcl‐1. CONCLUSIONS Galiellalactone induced growth inhibition and apoptosis in androgen‐insensitive PCa cells expressing p‐Stat3. We suggest that galiellalactone is a potential anti‐tumor lead against hormone‐refractory PCa with constitutively active Stat3. Prostate 68: 269–280, 2008. © 2007 Wiley‐Liss, Inc.