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Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells
Y. Li, K.S. Koeneman / Urologic Oncology: Seminars and Original Investigations 26 (2008) 98 –112
107
Commentary In advanced prostate cancer, the cells are “androgen-independent” (AICaP), or “androgen refractory”: cancer cells do not required androgen to support their growth anymore. In clinical terms, androgen ablation regime is no longer effective. However, without androgen ligand stimulation (testosterone or dihydrotestosterone), the androgen receptor is still likely to be involved in the recurrence of most prostate cancer. There could be several mechanisms, inducing traditional “ligand independent” AR activation: AR gene amplification, mutation, overexpression of androgen receptors or coactivators, and cross-talk with tyrosine kinases such as HER2. This article focused on the activated Cdc42-associated tyrosine kinase Ack1. The androgen-dependent cell line, LNCaP, developed androgen independence in castrated mice when transfected with constitutively activated Ack vector. The primary AICaP displayed 5-fold increase of Ack1, but not in benign prostate hyperplasia tissue. In 49 different human prostate samples, tyrosine phosphorylated AR was detected in 8 of 18 (⬃44%) AICaP tumor, but not in 13 androgen-dependent tumor, and 18 benign prostate hyperplasia tissue samples. The Ack1 and AR level were strongly correlated. Evidence showed activated Ack1 directly bound to AR in the N-terminal. Ack is apparently required for the expression of androgen-dependent genes, such as PSA and hK2, and is recruited to the androgen response element (ARE) of these genes. In the heregulin/ HER2 signaling pathway, Ack1 was a necessary intermediary in heregulin-dependent AR phosphorylation. These findings suggest Ack1 is a potential target for developing treatment of prostate cancer. doi:10.1016/j.urolonc.2007.11.019 Yingming Li, M.D., Kenneth S. Koeneman, M.D.
Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. Scott M. Dehm, Donald J. Tindall, Departments of Urology, Biochemistry, and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN. J Biol Chem 2006;281:27882–93 Androgen ablation inhibits androgen receptor (AR) activity and is an effective treatment for advanced prostate cancer (PCa). Invariably, PCa relapses in a form resistant to further hormonal manipulations. Although this stage of the disease is androgen-refractory, or androgen depletion-independent (ADI), most tumors remain AR-dependent through aberrant mechanisms of AR activation. We employed the LNCaP/C4-2 model of PCa progression to study AR activity in androgen-dependent and ADI PCa cells. In this report, we show that the AR is transcriptionally inactive in androgen-dependent LNCaP cells in the absence of androgens. However, in ADI C4-2 cells, the AR displays a high level of constitutive, androgen-independent transcriptional activity. To study the mechanisms of ligand dependent and ligand-independent AR activation in these AR-expressing cells, we generated a reporter system based on swapping the DNA binding domain of the AR with the DNA binding domain of the yeast Gal4 transcription factor. In androgen-dependent PCa cells, the well characterized C-terminal AR activation function-2 (AF-2) domain was critical for strong, ligand-dependent activity. Conversely, in ADI PCa cells, constitutive, ligand-independent AR activity was AF-2- independent but instead dependent on N-terminal AR domains. Importantly, the ligand- and AF-2-independent mode of AR activation observed in ADI PCa cells was completely resistant to the antiandrogen, bicalutamide. Our data thus demonstrate that the AR can inappropriately activate transcription in ADI PCa cells via mechanisms that are resistant to castration and AR antagonism, the 2 modes of androgen ablation used to treat advanced PCa.
Commentary Androgen receptor activity is still maintained in a ligand-independent conditions (low testosterone) including AR mutation or overexpression, altered activity of coregulators, or cross-talk with activated signal transduction pathways. In this paper, the functional study of androgen receptor (AR) in human prostate cancer lines LNCaP and C4-2, which are isogenic but are different in androgen dependency, is investigated. This study indicated bicalutamide is unable to inhibit AF-2-independent AR activity. This paper provides underlying mechanisms of ligand-dependent and -independent AR activity in both androgen independent and androgen dependent human prostate cancer cell lines, and could be a crucial guide to develop future new targets in treating prostate cancer. doi:10.1016/j.urolonc.2007.11.020 Yingming Li, M.D., Kenneth S. Koeneman, M.D.
Phosphoinositide 3-kinase-independent nongenomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains. Cinar B, Mukhopadhyay NK, Meng G, Freeman MR, Urological Diseases Research Center, Departments of Urology, Surgery, Biological Chemistry, and Molecular Pharmacology, Children’s Hospital Boston, Harvard Medical School, Boston, MA. J Biol Chem 2007;282:29584 –93. The serine-threonine kinase, Akt1/protein kinase Ba is an important mediator of growth, survival and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft
107
Commentary In advanced prostate cancer, the cells are “androgen-independent” (AICaP), or “androgen refractory”: cancer cells do not required androgen to support their growth anymore. In clinical terms, androgen ablation regime is no longer effective. However, without androgen ligand stimulation (testosterone or dihydrotestosterone), the androgen receptor is still likely to be involved in the recurrence of most prostate cancer. There could be several mechanisms, inducing traditional “ligand independent” AR activation: AR gene amplification, mutation, overexpression of androgen receptors or coactivators, and cross-talk with tyrosine kinases such as HER2. This article focused on the activated Cdc42-associated tyrosine kinase Ack1. The androgen-dependent cell line, LNCaP, developed androgen independence in castrated mice when transfected with constitutively activated Ack vector. The primary AICaP displayed 5-fold increase of Ack1, but not in benign prostate hyperplasia tissue. In 49 different human prostate samples, tyrosine phosphorylated AR was detected in 8 of 18 (⬃44%) AICaP tumor, but not in 13 androgen-dependent tumor, and 18 benign prostate hyperplasia tissue samples. The Ack1 and AR level were strongly correlated. Evidence showed activated Ack1 directly bound to AR in the N-terminal. Ack is apparently required for the expression of androgen-dependent genes, such as PSA and hK2, and is recruited to the androgen response element (ARE) of these genes. In the heregulin/ HER2 signaling pathway, Ack1 was a necessary intermediary in heregulin-dependent AR phosphorylation. These findings suggest Ack1 is a potential target for developing treatment of prostate cancer. doi:10.1016/j.urolonc.2007.11.019 Yingming Li, M.D., Kenneth S. Koeneman, M.D.
Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. Scott M. Dehm, Donald J. Tindall, Departments of Urology, Biochemistry, and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN. J Biol Chem 2006;281:27882–93 Androgen ablation inhibits androgen receptor (AR) activity and is an effective treatment for advanced prostate cancer (PCa). Invariably, PCa relapses in a form resistant to further hormonal manipulations. Although this stage of the disease is androgen-refractory, or androgen depletion-independent (ADI), most tumors remain AR-dependent through aberrant mechanisms of AR activation. We employed the LNCaP/C4-2 model of PCa progression to study AR activity in androgen-dependent and ADI PCa cells. In this report, we show that the AR is transcriptionally inactive in androgen-dependent LNCaP cells in the absence of androgens. However, in ADI C4-2 cells, the AR displays a high level of constitutive, androgen-independent transcriptional activity. To study the mechanisms of ligand dependent and ligand-independent AR activation in these AR-expressing cells, we generated a reporter system based on swapping the DNA binding domain of the AR with the DNA binding domain of the yeast Gal4 transcription factor. In androgen-dependent PCa cells, the well characterized C-terminal AR activation function-2 (AF-2) domain was critical for strong, ligand-dependent activity. Conversely, in ADI PCa cells, constitutive, ligand-independent AR activity was AF-2- independent but instead dependent on N-terminal AR domains. Importantly, the ligand- and AF-2-independent mode of AR activation observed in ADI PCa cells was completely resistant to the antiandrogen, bicalutamide. Our data thus demonstrate that the AR can inappropriately activate transcription in ADI PCa cells via mechanisms that are resistant to castration and AR antagonism, the 2 modes of androgen ablation used to treat advanced PCa.
Commentary Androgen receptor activity is still maintained in a ligand-independent conditions (low testosterone) including AR mutation or overexpression, altered activity of coregulators, or cross-talk with activated signal transduction pathways. In this paper, the functional study of androgen receptor (AR) in human prostate cancer lines LNCaP and C4-2, which are isogenic but are different in androgen dependency, is investigated. This study indicated bicalutamide is unable to inhibit AF-2-independent AR activity. This paper provides underlying mechanisms of ligand-dependent and -independent AR activity in both androgen independent and androgen dependent human prostate cancer cell lines, and could be a crucial guide to develop future new targets in treating prostate cancer. doi:10.1016/j.urolonc.2007.11.020 Yingming Li, M.D., Kenneth S. Koeneman, M.D.
Phosphoinositide 3-kinase-independent nongenomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains. Cinar B, Mukhopadhyay NK, Meng G, Freeman MR, Urological Diseases Research Center, Departments of Urology, Surgery, Biological Chemistry, and Molecular Pharmacology, Children’s Hospital Boston, Harvard Medical School, Boston, MA. J Biol Chem 2007;282:29584 –93. The serine-threonine kinase, Akt1/protein kinase Ba is an important mediator of growth, survival and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft