Abstract B109: Aldo-keto reductase(AKR) 1C3 expression is frequently observed in human prostate cancer cases after androgen therapy and promotes prostate cancer cell growth in castrated mice model.

Abstract

Abstract Introduction: Prostate cancer (PCa) is the most common malignancies and the second leading cause of death of men in US. Because PCa require androgen for its growth, anti-androgen therapy is favored for treating advanced PCa. Although anti-androgen therapy is initially effective for most PCa cases, virtually all of the cases will relapse after certain period of treatment. Recently several studies have revealed that androgen level was elevated in prostate tumor tissue even after anti-androgen therapy, while serum androgen level was reduced. In human male, the major sauce of androgen production is the testis. In addition adrenal glands also produce androgen in lesser extent. However adrenal androgens, dehydroepiandrosterone (DHEA), have weaker activity compared with testicular androgen, testosterone. DHEA could be converted to testosterone by only two enzymes, AKR1CE and HSD3B2, normally expressed in the testis. Recently it has been reported that AKR1C3 and HSD3B2 were over-expressed in prostate cancer tissue after anti-androgen therapy. However the precise origin of their production and biological relevance of these enzymes for androgen-independent PCa progression have yet to be clarified. Method: Seventy cases who received prostatectomy for PCa in our hospital were selected. Among the cases examined, 19 cases were treated with anti-androgen therapy prior to the prostatectomy. The expression of AKR1C3 and HSD3B in PCa tissues were examined immunohistochemically. The expression of AKR1C3 were also examined by Western blot in three androgen dependent PCa cell lines, LNCap, VCap and MDA-PCa2B, and one independent PCa cell line, PC3. For castrated mice model, one million (1×10∘6) of LNCap cells transduced with Mock or AKR1C3 (LNCap-mock or AKR1C3) by lenti-virus system were transplanted in mammary fat pad of intact or castrated nude mice. The tumor sizes were measured weekly, and developed tumors were histologically examined 5 weeks after implantation. Results: In human PCa cases, AKR1C3 expression was observed in 18 of 70 (25.7%) cases. The frequency of AKR1C3 expression was higher (p<0.01) in the cases that received anti-androgen therapy prior to prostatectomy (11/19; 57.9%) compared with the cases without prior therapy (7/58; 12.1%). No significant difference in terms of frequency of expression was observed in HSD3B2 (15/19; 78.9% vs. 45/58; 77.6%). In normal growth condition, AKR1C3 expression was observed in VCap and PC3, but not in LNCap or MDA-PCa2b. The AKR1C3 expression was enhanced or induced in VCap and LNCap in hormone depleted condition. Adione, which can be converted to testosterone by AKR1C3, stimulated LNCap-AKR1C3 growth but not LNCap-Mock. In castrated mice model, all the cases (6/6) of LNCap-AKR1C3 developed tumor, while only one out of five (1/5) case of LNCap-Mock did after 5 weeks of transplantation. Conclusion: AKR1C expression might be induced by anti-androgen therapy and could facilitate tumor cell proliferation in androgen depleted condition. Thus the molecular targeting therapy against AKR1C3, combination with ordinary anti-androgen therapy, will be promising for treating PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B109.