Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Xin L, Teitell MA, Lawson DA, Kwon A, Mellinghoff IK, Witte ON, Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA

Research output: Contribution to journalArticle

Abstract

Classic work by Huggins and Hodges demonstrated that human prostate cancer regresses dramatically during antihormonal therapy but recurs frequently with androgen independence. Perturbations in the androgen receptor (AR) and PTEN-AKT signaling axes are significantly correlated with the progression of prostate cancer. Genetic alterations of the AR cause receptor hypersensitivity, promiscuity, and androgen-independent receptor transactivation. Prostate cancers maintain an elevated AKT activity through the loss of PTEN function or the establishment of autocrine signaling by growth factors and cytokines. We used an in vivo prostate regeneration system to investigate the biological potency of the potential crosstalk between these two signal transduction pathways. We demonstrate a direct synergy between AKT and AR signaling that is sufficient to initiate and progress naive adult murine prostatic epithelium to frank carcinoma and override the effect of androgen ablation. Both genotropic and nongenotropic signals mediated by AR are essential for this synergistic effect. However, phosphorylation of AR by AKT at Ser-213 and Ser-791 is not critical for this synergy. These results suggest that more efficient therapeutics for advanced prostate cancer may need to target simultaneously AR signaling and AKT or the growth factor receptor tyrosine kinases that activate AKT.

Original languageEnglish (US)
Pages (from-to)177
Number of pages1
JournalUrologic Oncology: Seminars and Original Investigations
Volume25
Issue number2
DOIs
StatePublished - Mar 2007
Externally publishedYes

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Androgen Receptors
Microbiology
Allergy and Immunology
Molecular Biology
Prostatic Neoplasms
Medicine
Androgens
Autocrine Communication
Growth Factor Receptors
Protein-Tyrosine Kinases
Transcriptional Activation
Prostate
Regeneration
Signal Transduction
Intercellular Signaling Peptides and Proteins
Hypersensitivity
Epithelium
Phosphorylation
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

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title = "Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Xin L, Teitell MA, Lawson DA, Kwon A, Mellinghoff IK, Witte ON, Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA",
abstract = "Classic work by Huggins and Hodges demonstrated that human prostate cancer regresses dramatically during antihormonal therapy but recurs frequently with androgen independence. Perturbations in the androgen receptor (AR) and PTEN-AKT signaling axes are significantly correlated with the progression of prostate cancer. Genetic alterations of the AR cause receptor hypersensitivity, promiscuity, and androgen-independent receptor transactivation. Prostate cancers maintain an elevated AKT activity through the loss of PTEN function or the establishment of autocrine signaling by growth factors and cytokines. We used an in vivo prostate regeneration system to investigate the biological potency of the potential crosstalk between these two signal transduction pathways. We demonstrate a direct synergy between AKT and AR signaling that is sufficient to initiate and progress naive adult murine prostatic epithelium to frank carcinoma and override the effect of androgen ablation. Both genotropic and nongenotropic signals mediated by AR are essential for this synergistic effect. However, phosphorylation of AR by AKT at Ser-213 and Ser-791 is not critical for this synergy. These results suggest that more efficient therapeutics for advanced prostate cancer may need to target simultaneously AR signaling and AKT or the growth factor receptor tyrosine kinases that activate AKT.",
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