Stromal Androgen Receptor in Prostate Development and Cancer

Singh, Mandeep; Jha, Ruchi; Melamed, Jonathan; Shapiro, Ellen; Hayward, Simon W.; Lee, Peng

doi:10.1016/j.ajpath.2014.06.022

Cited by 69 publications

(63 citation statements)

References 79 publications

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“…However, the regulation of stromal AR expression may not be carried out by the same mechanism operating in the epithelia. This notion is supported by the observation that stromal AR expression progressively decreases during malignant transformation, differing from the increased AR expression in the malignant epithelia (Singh et al 2014). In addition, the differential expression of AR-associated coregulators or transcription factors between stromal and epithelial cells may also cause the differences in their regulatory mechanisms of AR function.…”

Section: :8supporting

confidence: 60%

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

Hsiao¹,

Huang²,

Hung³

et al. 2016

Endocrine-Related Cancer

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Androgen receptor (AR) is a steroid hormone receptor that functions as a transcription factor for regulating cell growth and survival. Aberrant AR function becomes a risk factor for promoting the progression of prostate cancer (PCa). In this study, we examined the roles of proline-rich tyrosine kinase 2 (PYK2) and ribosomal S6 kinase 1 (S6K1) in regulating AR expression and activity and growth properties in PCa cells. Compared with normal prostate tissues, PCa tumors exhibited high levels of PYK2 and S6K1 expression. Furthermore, the expression levels of PYK2 and S6K1 were significantly correlated with nuclear AR expression in PCa tissues. We further found the association between PYK2, S6K1, and AR in their protein expression and phosphorylation levels among normal prostate PZ-HPV-7 cells and prostate cancer LNCaP and 22Rv1 cells. Overexpression of the wild-type PYK2 in PZ-HPV-7 and LNCaP cells promoted AR and S6K1 expression and phosphorylation as well as enhanced cell growth. In contrast, expression of the mutated PYK2 or knockdown of PYK2 expression in LNCaP or 22Rv1 cells caused reduced expression or phosphorylation of AR and S6K1 as well as retarded cell growth. Under an androgen-deprived condition, PYK2-promoted AR expression and phosphorylation and PSA production in LNCaP cells can be abolished by knocking down S6K1 expression. In summary, our data suggested that PYK2 via S6K1 activation modulated AR function and growth properties in PCa cells. Thus, PYK2 and S6K1 may potentially serve as therapeutic targets for PCa treatment.

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Section: :8supporting

confidence: 60%

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

Hsiao¹,

Huang²,

Hung³

et al. 2016

Endocrine-Related Cancer

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“…In prostate epithelium, androgen receptor (AR) activity promotes proliferation 254 , but in the stroma, AR expression and activation by androgen binding inhibits prostate epithelial proliferation, whereas loss of AR in the stroma correlates with prostate cancer progression, although it is unknown how this observed phenomenon is manifested (please insert reference: Singh et al 2014). This phenomenon suggests that bipolar androgen therapy (introduction of supraphysiological levels of androgen after androgen deprivation therapy) could be an effective therapeutic strategy 255 .…”

Section: Effects Of Tumour Stroma On Therapymentioning

confidence: 99%

Targeting the tumour stroma to improve cancer therapy

2018

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Cancers are not merely composed of cancer cells alone and, instead, are complex ‘ecosystems’ comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistroma agents. Herein, we provide an overview of the advances in understanding the complex cancer cell–tumour stroma interactions, and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.

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“…During prostate carcinogenesis and progression, the stromal cells begin to lose AR expression as early as at the stage of high-grade prostatic intraepithelial neoplasia. 19) Increasing evidences pointed that AR was a critical mediator for anti-prostate cancer. [20][21][22] In view of this, researchers tended to explore agents to antagonize AR as improved therapeutic methods for prostatic cancer.…”

Section: Discussionmentioning

confidence: 99%

<i>Artesunate</i> Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

Wang¹,

Wang²,

et al. 2017

Biological & Pharmaceutical Bulletin

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Prostatic cancer (PCa) is a leading cause of cancer related death in males and is often regarded as a kind of androgen-sensitive cancer. Artesunate (ART), a semi-synthetic derivative of the Chinese herb Artemisia annua, is such an anti-cancer agent. However, the effects and mechanism of ART on PCa cells remains unclear. The study aims to elaborate the mechanism of the involvement of androgen receptor (AR) in antiprostatic cancer (PCa) of artesunate (ART). PCa cells 22rvl were used in vivo and in vitro, and the viability and apoptosis were conducted using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, respectively. Ectopic expressions of AR and DNA methyltransferase (DNMT) were detected in cells in overexpression or interference of AR or DNMT3b. ART dose-dependently suppressed tumor growth, inhibited cell viability, enhanced apoptosis, decreased AR expression, and increased the expression and the catalytic activity of DNMT3b in 22rv1 cells either in transplanted mice or in vitro. Furthermore, AR downregulated DNMT3b expression, and overexpression of AR or interference of DNMT3b could reverse ART-induced cytotoxicity and apoptosis in 22rvl cells, whereas overexpression of DNMT3b could not change the effect profiles of ART on the cells. The results indicated that ART suppressed tumor growth of prostatic cancer cells through AR-DNMT3b pathway, underlying ART will allow for the utilization of this Chinese therapeutic agent for the potential treatment of prostate cancer.Key words artesunate; prostatic cancer; androgen receptor; DNA methyltransferase; apoptosis Prostatic cancer (PCa) is the most common cause of cancerrelated death in males. Morbidity and mortality of PCa underscore the need for novel treatment options. Although improved therapies have been recently developed to treat and prevent PCa, prostate cancer still remains refractory disease. Lately, herbs and phytochemicals 1) have been attractive as therapeutic agents for tumorigenesis suppression. Understanding how the production of these Chinese herbs is regulated during cancer progression would help develop new cancer therapeutic strategy.Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART has been revealed remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P. vivax malaria. With the recognition of ART, it has now been analyzed for its anti-cancer activity in various tissues-specificity. For example, Tran et al. found that enhancement of ART activity could effectively induce the apoptosis of breast cancer cells. 2)Moreover, ART was proved to be as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation action on tumor growth, metastasis.3) Recently, Michaelsen et al. clinically treated PCa patients with long-term Artemisia annua capsules via oral administration combined with shortterm ART inj...

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Stromal Androgen Receptor in Prostate Development and Cancer

Cited by 69 publications

References 79 publications

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

Targeting the tumour stroma to improve cancer therapy

<i>Artesunate</i> Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

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