Alternative DHT Synthesis Pathway Key in Prostate Cancer
Monday, August 1, 2011 (Last Updated: 08/02/2011)
MONDAY, Aug. 1 (HealthDay News) -- Dihydrotestosterone (DHT) synthesis from adrenal precursor steroids in castration-resistant prostate cancer (CRPC) bypasses testosterone synthesis, and occurs through an alternative pathway involving conversion of Δ4-androstenedione (AD) to 5α-androstanedione (5α-dione) by 5α-reductase isoenzyme-1 (SRD5A1), according to an experimental study published online July 27 in the Proceedings of the National Academy of Sciences.
Kai-Hsiung Chang, Ph.D., from the University of Texas Southwestern Medical Center in Dallas, and colleagues demonstrated that progression of prostate cancer to CRPC involves an alternative hormonal pathway of DHT synthesis from adrenal precursors that bypasses testosterone synthesis, and requires SRD5A1. The dominant DHT synthesis pathway was analyzed in six established human prostate cancer cell lines. Biopsies of metastatic CRPC tumors were examined to establish the preferred route for AD metabolism. Subcutaneous xenograft studies in surgically orchiectomized mice supplemented with testosterone and AD were carried out to investigate the requirements of the conventional versus alternative pathway for CRPC growth.
The investigators found that the major metabolic pathway from adrenal precursor steroids to DHT in CRPC bypasses testosterone. Instead, the transformation of AD to 5α-dione by SRD5A1 is required for DHT synthesis and tumor progression. The transition from hormone-naive prostate cancer to CRPC involves SRD5A1 up-regulation occurring concurrently with SRD5A isoenzyme-2 down-regulation. Human CRPC cell lines and fresh tissue obtained from human tumor metastases have an operational and dominant alternative pathway. Mouse xenograft models and SRD5A1 expression were found to be dependent upon this pathway.
"Our observation that DHT is synthesized through an alternative pathway involving conversion of AD to 5α-dione by SRD5A1 has broad implications for the development of new therapeutic agents and for determining mechanisms of resistance to hormonal therapies for CRPC," the authors write.
Hematology & Oncology
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