Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer

Abstract

Hormone therapies targeting androgen receptor signaling are the mainstay of treatment for patients with advanced prostate cancer. The length of clinical remission induced by hormone therapies varies substantially among treated patients. Why some patients progress rapidly after treatment while others benefit with prolonged remission is a question that remains unsolved. The androgen receptor signaling pathway is the key molecular determinant of castration resistance, and a key target for prostate cancer drug design. Recent advances in characterizing molecular processes leading to the development of castration-resistant prostate cancer, including the discovery of multiple androgen receptor splicing variants, offer opportunities for rational development of new clinical tools or approaches to predict, monitor or control/prevent prostate cancer progression in the castrate setting.

Figure 1. Hormone therapy regimens commonly used to treat advanced prostate cancer

The hypothalamus–pituitary axis controls testicular androgen synthesis by regulating release of LH. LHRH analogs disrupt this axis and leads to suppression of LH release. T is converted to DHT in the prostate by 5-α reductases (type I and II), which can be inhibited by finasteride and dutasteride. Adrenal androgens, mainly DHEA and DHEA-S, may be used by the prostate cells as precursors of androgens. Abiraterone and ketoconozole inhibit enzymes involved in steroid biosynthesis. AR: Androgen receptor; DHEA: Dehydroepiandrosterone; DHEA-S: Dehydroepiandrosterone sulfate; DHT: Dihydrotestosterone; GnRH: Gonadotropin-releasing hormone; LH: Luteinizing hormone; LHRH: Luteinizing hormone-releasing hormone; T: Testosterone.

Figure 2. The human androgen receptor gene, transcript and protein structure

Canonical exons and coding regions (from the ATG translation start site to the TGA stop codon) in AR mRNA are indicated. The peptide sequence positions in relation to the four AR domains are marked. AR: Androgen receptor; DBD: DNA-binding domain; LBD: Ligand-binding domain; NLS: Nuclear localization signal; NTD: N-terminal domain.

Figure 3. Differences in AR signaling mediated by the full-length AR with intact LBD, and an AR variant that lacks LBD

Activation of the full-length AR requires binding of androgens. Upon androgen binding, cytoplasmic AR undergoes conformational changes, dissociates from the HSP90 chaperone, and enters into the nuclei to initiate gene transcription. The AR splicing variant lacks the ligand-binding domain and is not expected to associate with cytoplasimic chaperones, leading to ligand-independent nuclear localization and activation. While the full-length AR forms homodimers, it is not known whether AR variants also undergo dimerization. AR: Androgen receptor; DHT: Dihydrotestosterone; P: Prostate-specific antigen; T: Testosterone.