Immunohistochemical examination of the mTORC1 pathway in high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa): A tissue microarray study (TMA)

Evren, Sevan; Dermen, Arthur; Lockwood, Gina; Fleshner, Neil; Sweet, Joan

doi:10.1002/pros.21178

Cited by 16 publications

(22 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…mTOR was detected mostly in the cytoplasm of epithelial cells from benign glands and cancer cells of tumor foci, with low or undetectable expression in stromal cells (Fig. 6A), which is consistent with previous studies (Dai et al 2009;Evren et al 2010;Sutherland et al 2014). No difference in mTOR cytoplasmic staining intensity between peri-tumoral and tumor samples was found (Supplemental Fig.…”

Section: Nuclear Mtor Levels Correlate With Pca Progressionsupporting

confidence: 91%

“…The mTOR signaling pathway is hyperactivated in PCa tumors compared with peri-tumoral or benign prostate tissues (Kremer et al 2006;Evren et al 2010;Sutherland et al 2014). In fact, alterations leading to hyperactivation of mTOR and its upstream regulators (PI3K/Akt), such as loss of PTEN, are among the most frequent genomic alterations in metastatic CRPC (Taylor et al 2010;Grasso et al 2012;Robinson et al 2015;Kumar et al 2016).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

View full text Add to dashboard Cite

Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

show abstract

Section: Nuclear Mtor Levels Correlate With Pca Progressionsupporting

confidence: 91%

mentioning

confidence: 99%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…mTOR is closely associated with the genesis and development of cancer. Previous studies have demonstrated that mTOR protein expression is significantly upregulated in various types of cancer tissue, including PC, liver cancer, cervical cancer, colorectal cancer, lung adenocarcinoma, esophageal squamous carcinoma, non-small cell lung cancer and extra hepatic bile duct carcinoma (25,28). The results of the present study demonstrated that treatment with cucurbitacin E induced mTOR protein expression inhuman PC cells.…”

Section: Discussionsupporting

confidence: 71%

Cucurbitacin E induces apoptosis of human prostate cancer cells via cofilin-1 and mTORC1

Gao

Qiang

et al. 2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. Cucurbitacin E is an important member of the cucurbitacin family and exhibits inhibitory effects in various types of cancer. Cucurbitacin is a potential antineoplastic drug; however, its anticancer effect in human prostate cancer (PC) remains unknown. The aim of the present study was to determine whether the effect of cucurbitacin E on the cell viability and apoptosis of the human PC cell line, LNCaP, was mediated by cofilin-1-and mammalian target of rapamycin (mTOR). The results of the present study demonstrated that cucurbitacin E significantly exhibited cytotoxicity, suppressed cell viability (P<0.0001) and induced apoptosis (P=0.0082) in LNCaP cells. In addition, it was demonstrated that treatment with cucurbitacin E significantly induced cofilin-1 (P=0.0031), p-mTOR (P=0.0022), AMP-activated protein kinase (AMPK; P=0.0048), cellular tumor antigen p53 (p53; P=0.0018) and caspase-9 (P=0.0026) protein expression in LNCaP cells, suggesting that cucurbitacin E exerts its effects on LNCaP cells through cofilin-1, mTOR, AMPK, p53 and caspase-9 signaling. These results suggested that cucurbitacin E maybe used as a therapeutic agent in the treatment of human PC.

show abstract

“…Two recent reports using TMAs and quantitative IHC, for the study of malignant peripheral nerve sheath tumours [53] and malignant pleural mesothelioma [54], showed the approach to be an effective high-throughput tool for the investigation of protein expression. Moreover, multiplex IHC and TMAs were successfully used together to examine the mTORC1 pathway in high-grade prostate intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa) [55].…”

Section: Immunohistochemical Staining Of Tissue Microarraysmentioning

confidence: 99%

In Situ Proteomic Analysis of Histological Sections

Zhu¹,

Du²,

Blackler³

et al. 2012

View full text Add to dashboard Cite

To fully integrate molecular analysis with histology, it is essential to further develop and evaluate in situ tissue section-based technologies that are sensitive, quantitative, and high-throughput. In the proteomics field, immunohistochemistry (IHC) is the method of choice for in situ measurement of protein levels in histological sections. However, matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) and related methods are emerging as additional multiplex in situ protein analysis tools. In this review, we discuss the application of these techniques in biomedical research and describe three newly developed technologies: multiplex tissue immunoblotting, indirect layered peptide array, and layered electrophoretic transfer (LET). In particular, we emphasize the LET technology as a novel in situ separation tool that allows for a more comprehensive proteomic analysis of a tissue sample while maintaining the important two-dimensional histological architecture.

show abstract

Immunohistochemical examination of the mTORC1 pathway in high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa): A tissue microarray study (TMA)

Abstract: mTOR inhibitors may be an effective treatment for HGPIN and PCa. The extent of mTOR expression in an individual patient would determine the effective use of mTOR inhibitors as a potential therapeutic strategy.

Cited by 16 publications

References 32 publications

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Cucurbitacin E induces apoptosis of human prostate cancer cells via cofilin-1 and mTORC1

In Situ Proteomic Analysis of Histological Sections

Contact Info

Product

Resources

About