Androstenedione Is the Preferred Androgen Source in Hormone Refractory Prostate Cancer—Letter

Home , Androgen, Androstanedione, Dihydrotestosterone

Clinical Cancer Letter to the Editor Research

Nima Shariﬁ1,2,3 and Richard J. Auchus4

Fankhauser and colleagues recently report on pathways of 96 hours. First, a time course is necessary to determine of androgen metabolism and dihydrotestosterone (DHT) reaction sequence. Second, 5a-dione was never measured. synthesis in prostate cancer (1). Two possibilities for the fate Third, their conclusions fail to account for the possibility of the adrenal steroid androstenedione in peripheral tissues that transient intermediates are metabolized without accu- are conversion to testosterone or 5a-reduction to 5a- mulation. Ninety-six hours incubation in their experiments androstanedione (5a-dione), the latter of which we previ- is a late time point that may miss the appearance of ously reported predominates in multiple cell line models intermediate metabolites and at which time the majority and clinical metastatic castration-resistant prostate cancer of 5a-reduced androgens (including DHT) are often found tissues, promotes tumor progression (2), and is probably conjugated by glucuronidation and thereby not extracted in driven by the upregulation of 5a-reductase isoenzyme-1, the organic phase, unless there is treatment with glucuron- which prefers androstenedione over testosterone as its idase, which was not reported in this study. Contrary to their substrate (3). conclusions, the data in Fig. 2 show that AD is primarily In the Statement of Translational Relevance, Fankhauser metabolized to the 5a-reduced metabolite androsterone, and colleagues state they have "performed a comprehensive which occurs through the intermediacy of 5a-dione. screen of the steroidogenic potential" and that they "found Because the 5a-reduced androgens are reversibly intercon- no evidence of significant contribution from the previously verted in cells, it is likely that DHT is formed but is a described ‘backdoor’ or ‘5a-dione’ pathway to androgen transient product. synthesis." Unfortunately, their experimental design cannot Furthermore, we were most concerned that "no evi- determine the order of these metabolic steps, and, thus, dence" of conversion to 5a-dione in their "comprehensive their data cannot support their conclusions. Their bold screen" was concluded despite the fact that they did not conclusions were drawn from data with experiments that even look for 5a-dione. This is the equivalent of stating incubated prostatic tissues with steroid precursors with a with certainty that there is nothing behind door #2 with- single technical replicate per patient, for a single time point out ever opening the door. These authors state that they did not "detect any significant production of DHT...dir- ectly from androstenedione by the ‘5a-dione’ pathway 1Department of Cancer Biology, Lerner Research Institute, Cleveland (Supplementary Fig. S1)...." However, the referenced Sup- Clinic, Cleveland, Ohio. 2Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio. 3Department of Solid plementary Figure shows no data from androstenedione Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, incubations and again did not assess for 5a-dione. Ohio. 4Division of Metabolism, Diabetes, and Endocrinology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Disclosure of Potential Conflicts of Interest Corresponding Author: Nima Sharifi, Department of Cancer Biology, R.J. Auchus reports receiving other commercial research support from Mail Stop NB40, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Janssen Pharmaceuticals and is a consultant/advisory board member for Avenue, Cleveland, OH 44195. Phone: 216-445-9750; Fax: 216-445-6269; BioMarin Pharmaceuticals, Tokai Pharmaceuticals, and Viamet Pharmaceu- E-mail: [email protected] ticals. No potential conflicts of interest were disclosed by the other author. doi: 10.1158/1078-0432.CCR-14-1123 Received May 2, 2014; accepted May 18, 2014; published online 2014 American Association for Cancer Research. September 15, 2014.

References 1. Fankhauser M, Tan Y, Macintyre G, Haviv I, Hong MK, Nguyen T, et al. castration-resistant prostate cancer. Proc Natl Acad Sci U S A Canonical androstenedione reduction is the predominant source of 2011;108:13728–33. signalling androgens in hormone refractory prostate cancer. Clin Cancer 3. Thigpen AE, Cala KM, Russell DW. Characterization of Chinese hamster Res 2014 Apr 25. [Epub ahead of print]. ovary cell lines expressing human steroid 5 alpha-reductase isozymes. 2. Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, J Biol Chem 1993;268:17404–12. et al. Dihydrotestosterone synthesis bypasses testosterone to drive

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Nima Sharifi and Richard J. Auchus

Clin Cancer Res 2014;20:4971.

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