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"Getting From Here to There"-Mechanisms and Limitations to the Activation of the Androgen Receptor in Castration-Resistant Prostate Cancer
  1. Nima Sharifi, MD*,
  2. Michael J. McPhaul, MD,
  3. Richard J. Auchus, MD, PhD
  1. From the Divisions of *Hematology and Oncology, and †Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
  1. Received August 18, 2010, and in revised form September 9, 2010.
  2. Accepted for publication September 9, 2010.
  3. Reprints: Nima Sharifi, MD, Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8852. E-mail: nima.sharifi{at}utsouthwestern.edu.
  4. This publication has been funded in part by a Howard Hughes Medical Institute Physician-Scientist Early Career Award, a Prostate Cancer Foundation Young Investigator Award, grant number UL1RR024982 from the National Center for Research Resources, a component of the National Institutes of Health and National Institutes of Health Roadmap for Medical Research, and from grant number PC080193 from the US Army Medical Research and Materiel Command to NS. RJA is supported by a Clinical Scientist Award in Translational Research from the Burroughs-Wellcome Fund (1005954) and by the Charles A. and Elizabeth Ann Sanders Chair in Translational Research.

Abstract

Despite the clinical regression that typifies the initial response of advanced prostate cancer to gonadal testosterone depletion, tumors eventually progress. However, evidence supports the concept that signaling via the androgen receptor (AR) is important in progression to castration-resistant prostate cancer (CRPC).

Steroid hormones are synthesized from cholesterol in a series of tightly regulated steps involving the cleavage of carbon-carbon bonds, the introduction of functional groups derived from activated molecular oxygen, and the oxidation and reduction of carbon-carbon and carbon-oxygen bonds. In the adrenal cortex and gonads, steroidogenesis is tightly regulated, very efficient, and highly directional. In contrast, steroid metabolism in peripheral tissues is characterized by competing enzymes and pathways, low efficiency, and great variability. Many steps are mechanistically and functionally irreversible, but some are not, and the repertoire of specific enzymes, intracellular redox state, and access to hormone precursors all contribute to steroid flux and accumulation.

The investigation of steroid metabolizing enzymes in CRPC often assumes that the pathways and the patterns of metabolism mirror those defined in the adrenals and the gonads and validated by human deficiency syndromes. Unfortunately, several potential pathways using different enzymes might contribute substantially to androgen synthesis in CRPC. Finally, a number of mechanisms have been reported by which the AR is activated independent of ligand. Recent observations have suggested that AR forms with constitutive activity occur in CRPC, stimulating transcription without a requirement for ligand. This overview outlines a broad view of how the mechanisms by which the AR may be activated, whether by alternate pathways of androgen synthesis or the production of alternate forms of the AR, with an emphasis on what aspects must be accounted for when using model systems to explore the biology of human prostate cancer.

Key Words
  • steroid metabolism
  • androgen receptor
  • androgens

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