Increased Androgen Receptor Activity Research Articles

Coactivator selective regulation of androgen receptor activity

The androgen receptor (AR) is a ligand activated nuclear receptor, which regulates transcription and stimulates growth of androgen dependent prostate cancer. To regulate transcription, AR recruits a series of coactivators that modify chromatin and facilitate transcription. However, information on ligand and target gene-specific requirements for coactivators is limited. We compared the actions of the p160 coactivators SRC-1 and SRC-3/RAC3 with SRA (steroid receptor RNA activator). All three coactivate AR in the presence of agonist as expected. However, overexpression of either SRC-1 or SRC-3 increased AR activity in response to the partial antagonist, cyproterone acetate, whereas SRA was unable to stimulate AR activity under these conditions. Using siRNA to reduce expression of these coactivators in LNCaP cells, we also found promoter specific requirement for these coactivators. SRC-3 is required for optimal androgen dependent induction of PSA, TMPRSS2, and PMEPA1 whereas SRA is required only for optimal induction of the TMPRSS2 gene. These data indicate that different groups of AR target genes have distinct requirements for coactivators and response to AR ligands.

Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1alpha levels contribute to emergence of an aggressive phenotype in prostate cancer.

Androgen Receptor (AR) -signaling plays a critical role in the development and progression of prostate cancer. Tumor microvasculature contributes to continual exposure of prostate cancer cells to hypoxia-reoxygenation, however, the role of hypoxia-reoxygenation in prostate cancer progression and modulation of AR signaling is not understood. In the present study, we evaluated the effects of hypoxia-reoxygenation in LNCaP cells, a line of hormone responsive human prostate cancer cells. Our results demonstrate that hypoxia-reoxygenation resulted in increased survival, higher clonogenicity, and enhanced invasiveness of these cells. Moreover, hypoxia-reoxygenation was associated with an increased AR activity independent of androgens as well as increased Hypoxia Inducible Factor (HIF-1α) levels and activity. We also observed that the activation of p38 MAP kinase pathway was an early response to hypoxia, and inhibition of p38 MAP kinase pathway by variety of approaches abolished hypoxia-reoxygenation induced increased AR activity as well as increased survival, clonogenicity, and invasiveness. These results demonstrate a critical role for hypoxia induced p38 MAP kinase pathway in androgen independent AR activation in prostate cancer cells, and suggest that hypoxia re-oxygenation may select for aggressive androgen-independent prostate cancer phenotype.

Is prostate cancer more common and more aggressive in African men?

The highest prostate cancer incidence and mortality rates in the world have been reported among Black African-American men (AAM) living in the United States of America. These rates are significantly higher for AAM compared to White (Caucasian) American men (CAM). However, prostate cancer is not the only malignancy which is more common in AAM compared to White American men or women. Although prostate cancer has the highest Black/White mortality ratio, it is not the only malignancy which has a higher mortality in AAM compared to CAM. Numerous reports have shown that AAM present with higher grade and stage tumors, higher serum PSA levels, and that they are less likely to receive definitive or curative treatment and have a worse prognosis compared with CAM. It has been suggested that prostate cancer is not only more common, but also more biologically aggressive in AAM compared with CAM. Hypotheses attempting to explain this include genetic differences, dietary factors, higher testosterone levels or increased androgen receptor activity. However, the majority of reports from the USA indicate that, when controlled for major prognostic factors, the outcome for clinically localized as well as advanced prostate cancer does not depend on race. Several studies have indicated that socioeconomic factors, decreased awareness of prostate cancer and limited access or decreased utilization of health care contribute to the poorer outcomes in AAM. Earlier studies have suggested that prostate cancer is relatively rare among indigenous Black men living in Africa. However, cancer incidence data in Africa are likely to underestimate the true rates because of underdiagnosis and underreporting. The frequency distribution of cancers in African countries, as well as more recent data indicate that prostate cancer is not rare among Black men living in Africa and that the incidence is probably similar to that of White men, although not as high as that reported for Black men living outside Africa. It is well documented that African men with prostate cancer present with more advanced disease and that palliative rather than curative treatment is used in the majority of patients. There are no reliable age-adjusted prostate cancer mortality rates available for African countries. However, there is as yet no evidence that prostate cancer in Black men living inside Africa is biologically more aggressive than in other populations.

Androgen receptor coregulators in prostate cancer: mechanisms and clinical implications.

The transcriptional activity of androgen receptor (AR) is modulated by coregulators that have a significant influence on a number of functional properties of AR, including the ligand specificity as well as the DNA binding capacity. Because androgens and AR have pivotal roles in the development and

Androgen receptor polymorphisms and risk of biochemical failure among prostatectomy patients.

Little is known about the role of inherited genotypes in prostate cancer (PC) progression. This prospective study evaluated the predictive value of androgen receptor (AR) polymorphisms (CAG and GGC repeats) among prostatectomy patients. We studied 354 patients registered at M. D. Anderson Cancer Center from 1991 to 2001. Kaplan-Meier and Cox proportional hazard analyses were used. During an average follow-up of 56 months, 66 (19%) post-prostatectomy patients experienced biochemical failure (BF). Patients with higher CAG repeats (CAG > or = 24) had significantly longer BF-free survival (BFFS) than those with fewer repeats (CAG < or = 23) (P = 0.04). Higher CAG repeats were significantly associated with lower BF risk among Whites and African Americans. Among Whites, longer CAG repeats (relative risk (RR) = 0.45, P = 0.03) and Gleason score > or = 8 (RR = 19.33, P = 0.005) remained significant BFFS predictors in multivariate analysis. GGC repeats were not associated with BF. Our data showed that an inherited polymorphism (CAG repeats) in the AR is related to differences in genetic susceptibility to BF, supporting the hypothesis that increased AR activity may play a role in PC progression.

Proteasomes Enhance Androgen Receptor Action

Proteasome inhibitors can elicit apoptosis in different cancer cells types. Lin et al. have explored the molecular details of this effect in prostate cancer cell lines where signals mediated by the steroid hormone androgen play a key role in cancer progression. The study reports that proteasome activity is required for androgen receptor (AR) activity. A link between AR activity and the ubiquitin-proteasome pathway had been suspected, as certain AR coregulators contain ubiquitin-protein ligase activity. Treatment of prostate cancer cells with a proteasome inhibitor suppressed AR transactivation and expression of target genes. A block in AR nuclear translocation and AR interaction with certain coregulators suggests that proteasomes may guide AR to its gene targets, as well as mediate interaction with its coregulators. The proteasome inhibitor did not affect the activity of the glucocorticoid receptor nor did it have a general toxic effect on cells. Overexpression of a proteasome core complex increased AR activity. The authors suggest that the ubiquitin-proteasome pathway may play a nonproteolytic role in modulating AR trafficking and recruitment of transcription factors. H. K. Lin, S. Altuwaljri, W. J. Lin, P.-Y. Kan, L. L. Collins, C. Chang, Proteasome activity is required for androgen receptor transcriptional activity via regulation of androgen receptor nuclear translocation and interaction with coregulators in prostate cancer cells. J. Biol. Chem. 277 , 36570-36476 (2002). [Abstract] [Full Text]