Androgens target prohibitin to regulate proliferation of prostate cancer cells

Gamble, Simon C.; Odontiadis, Michael; Waxman, Jonathan; Westbrook, Jules A.; Dünn, Michael J.; Wait, Robin; Lam, Eric W.‐F.; Bevan, Charlotte L.

doi:10.1038/sj.onc.1207444

Cited by 98 publications

(92 citation statements)

References 42 publications

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“…14). In support of this, we have previously demonstrated that the AR in these cells is capable of downregulating endogenous prohibitin protein in response to androgen stimulation, to a similar extent as seen in the LNCaP cell line (18).…”

Section: Resultssupporting

confidence: 60%

Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens

Whitaker

Hanrahan²,

Totty³

et al. 2004

Clinical Cancer Research

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Purpose: Antiandrogens are routinely used in the treatment of prostate cancer. Although they are known to prevent activation of the androgen receptor (AR), little is known about the mechanisms involved. This report represents the first study of the localization of wild-type AR following expression at physiologic relevant levels in prostate cells and treatment with androgen and antiandrogens.Experimental Design: We have characterized a cellular model for prostate cancer using in situ cellular fractionation, proteomics, and confocal microscopy and investigated the effect of antiandrogens in clinical use on the subcellular localization of the AR.Results: Different antiandrogens have diverse effects on the subcellular localization of the AR. Treatment with androgen results in translocation from the cytoplasm to the nucleoplasm, whereas the antiandrogens hydroxyflutamide and bicalutamide lead to reversible association with the nuclear matrix. In contrast, treatment with the antiandrogen cyproterone acetate results in AR association with cytoplasmic membranes and irreversible retention within the cytoplasm. In addition, we demonstrate that AR translocation requires ATP and the cytoskeleton, regardless of ligand.Conclusions: These results reveal that not all antiandrogens work via the same mechanism and suggest that an informed sequential treatment regime may benefit prostate cancer patients. The observed subnuclear and subcytoplasmic associations of the AR suggest new areas of study to investigate the role of the AR in the response and resistance of prostate cancer to antiandrogen therapy.

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Section: Resultssupporting

confidence: 60%

Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens

Whitaker

Hanrahan²,

Totty³

et al. 2004

Clinical Cancer Research

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“…Cell Proliferation Assays-Sulforhodamine B was used to assess proliferation of cells as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

Repression of Androgen Receptor Activity by HEYL, a Third Member of the Hairy/Enhancer-of-split-related Family of Notch Effectors

Lavery

Villaronga

Walker

et al. 2011

Journal of Biological Chemistry

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The Hairy/Enhancer-of-split-related with YRPW-like motif (HEY) family of proteins are transcriptional repressors and downstream effectors of Notch signaling. We previously reported that HEY1 and HEY2 selectively repress androgen receptor (AR) signaling in mammalian cell lines and have shown that in human tissue HEY1 is excluded from the nuclei in prostate cancer but not benign prostatic hyperplasia. We have now characterized a third member of this family, HEYL, which is a more potent repressor of AR activity. HEYL interacted with and repressed AR activation function-1 domain and competitively inhibited SRC1e activation of AR transcriptional activity. Using a cell line inducibly expressing exogenous HEYL, we showed that HEYL represses endogenous AR-regulated genes and reduces androgen-dependent prostate cancer cell growth. Using a transrepression assay, we identified both trichostatin-sensitive and -insensitive domains within HEYL; however, analysis of endogenous AR target genes suggested that HEYL represses AR activity through histone deacetylase I/II-independent mechanisms. Immunohistochemical analyses of tissue indicated that, in a fashion similar to that previously reported for HEY1, HEYL is excluded from the nuclei in prostate cancer but not adjacent benign tissue. This suggests that nuclear exclusion of HEY proteins may be an important step in the progression of prostate cancer.

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“…5,6 PHB can also inhibit steroidactivated nuclear receptors, such as the androgen receptor (AR) and estrogen receptor (ER). 7,8 PHB was reported to act as a potent transcriptional co-repressor of ERa and associate with estrogen-regulated promoters in the absence of hormone, dissociating after hormone treatment in the breast cancer cells. 8 PHB was reported to induce the anti-proliferative actions of estrogen antagonists in breast cancer cells and recruit BRG1-containing chromatin-remodeling complex to antagonist-bound AR in prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Prohibitin promotes androgen receptor activation in ER-positive breast cancer

Liu

Zhang

et al. 2017

Cell Cycle

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Prohibitin (PHB) is an evolutionarily conserved protein with multiple functions in both normal and cancer cells. Androgen receptor (AR) was reported to act as a different role in the ER-positive and ER-negative breast cancer. However, little is known about the role of PHB and whether PHB could regulate AR expression in the ER-positive breast cancer. Here, we determined the expression and clinical outcomes of PHB in breast cancer samples using 121 breast cancer tissues and published databases, and investigated the role of PHB in breast cancer cell growth, apoptosis and cell cycle arrest in the ER-positive breast cancer cells. We obtained the expression of PHB is significantly low in breast cancer samples, and low PHB expression positively correlated with poor prognosis of breast cancer. We detected that PHB could inhibit breast cancer cell proliferation, change cell cycle distribution and promote cell apoptosis in the ER-positive breast cancer cells. Moreover, we found PHB could significantly increase AR expression in both mRNA and protein levels in the ER-positive breast cancer cells. Additionally, a significant positive correlation between PHB and AR expression was identified in the 121 breast cancer tissues. PHB and AR expression are associated with prognosis in the ER-positive breast cancer patients. Our results indicate that PHB promotes AR activation in ER-positive breast cancer, making PHB and AR potential molecular targets for ER-positive breast cancer therapy.

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Androgens target prohibitin to regulate proliferation of prostate cancer cells

Cited by 98 publications

References 42 publications

Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens

Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens

Repression of Androgen Receptor Activity by HEYL, a Third Member of the Hairy/Enhancer-of-split-related Family of Notch Effectors

Prohibitin promotes androgen receptor activation in ER-positive breast cancer

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