Generation of Prostate Tumor–Initiating Cells Is Associated with Elevation of Reactive Oxygen Species and IL-6/STAT3 Signaling

Qu, Yi; Øyan, Anne Margrete; Liu, Runhui; Hua, Yaping; Zhang, Jigang; Hovland, Randi; Popa, Mihaela; Liu, Xiaojun; Brokstad, Karl Albert; Simon, Ronald; Molven, Anders; Lin, Biaoyang; Zhang, Weidong; McCormack, Emmet; Kalland, Karl‐Henning; Ke, Xisong

doi:10.1158/0008-5472.can-13-1560

Cited by 70 publications

(78 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These three related compound types have been found in propolis samples from Brazil [24], while cardols have been detected in poroplis from Thailand and Indonesia [15,25]. They most probably originate from Mangifera indica fruit bark and are known antifungal substances [15,26].…”

Section: Resultsmentioning

confidence: 99%

Omani propolis: chemical profiling, antibacterial activity and new propolis plant sources

Popova

Dimitrova

Al-Lawati

et al. 2013

Chemistry Central Journal

View full text Add to dashboard Cite

BackgroundPropolis (bee glue) is a resinous honeybee product having a long history of application in many countries as a traditional remedy for treating wounds, burns, soar throat, stomach disorders, etc. It has been proved to possess beneficial biological effects, including antimicrobial, antioxidant, anti-inflammatory, cytotoxic, antiulcer, and many others. Bees gather propolis from diverse resinous plant parts and in different phytogeographic regions its chemical composition might vary significantly. In this article we report the results of the first study on the chemical profiles of propolis from Oman, its plant origin and antibacterial activity.ResultsThe chemical profiles of Omani propolis extracts were obtained by GC-MS analysis after silylation. Over 50 individual compounds were identified in the samples, belonging to different compound types: sugars, polyols, hydroxy acids, fatty acids, cardanols and cardols, anacardic acids, flavan derivatives, triterpenes, prenylated flavanones and chalcones. The profiles were dissimilar from other known propolis types. They demonstrate that although Oman is not a large country, the plant sources of propolis vary significantly, even in the same apiary and the same season. Based on chemical profiles, and isolation and identification of major marker compounds (new propolis constituents), new plant sources of propolis were found: Azadiracta indica (neem tree) and Acacia spp. (most probably A. nilotica). The ethanol extracts of the studied propolis samples demonstrated activity against S. aureus (MIC < 100 μg. mL-1) and E. coli (MIC < 380 μg. mL-1).ConclusionOmani propolis is different form the known propolis types and demonstrates significant chemical diversity. Its most important plant source is the resin of Azadirachta indica, and as a result its typical components are С5-prenyl flavanones. Other plant sources have been identified, too, playing some role in resin collection by bees in Oman: Acacia spp. (most probably A. nilotica) and Mangifera indica. The results demonstrate also the potential of Omani propolis as antimicrobial.

show abstract

Section: Resultsmentioning

confidence: 99%

Omani propolis: chemical profiling, antibacterial activity and new propolis plant sources

Popova

Dimitrova

Al-Lawati

et al. 2013

Chemistry Central Journal

View full text Add to dashboard Cite

show abstract

“…Supportive cells include macrophages, fibroblasts, and mesenchymal stem cells that secrete growth factors and cytokines, such as IL6, and create a milieu enabling the cancer cells to acquire and retain stem-like properties (13)(14)(15). Recent reports point to transcriptional regulators, such NF-kB and STAT3, as key elements in the signaling pathways sustaining CSCs in human tumors (16)(17)(18). Constitutive activation of NF-kB is found in many tumors (19,20).…”

Section: Introductionmentioning

confidence: 99%

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

Civenni

Longoni

Costales

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-kB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKb and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-kB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKb and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-kB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. Thus, EC-70124 is a potent inhibitor of the NF-kB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806-18. Ó2016 AACR.

show abstract

“…We have previously published the stepwise generation of malignant prostate, mesenchymal EPT3-PT1 cells from benign epithelial EP156T cells by physiological adaptation and selection [23, 57–59]. In spite of detectable AR in EPT3-PT1 cells compared to its progenitor AR negative EP156T cells, EPT3-PT1 cells showed no androgen-dependent induction of AR and its classical luminal differentiation target genes.…”

Section: Resultsmentioning

confidence: 99%

An androgen response element driven reporter assay for the detection of androgen receptor activity in prostate cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

The androgen receptor (AR) transcription factor plays a key role in the development and progression of prostate cancer, as is evident from the efficacy of androgen-deprivation therapy, AR is also the most frequently mutated gene, in castration resistant prostate cancer (CRPC). AR has therefore become an even more attractive therapeutic target in aggressive and disseminated prostate cancer. To investigate mechanisms of AR and AR target gene activation in different subpopulations of prostate cancer cells, a toolkit of AR expressor and androgen response element (ARE) reporter vectors were developed. Three ARE reporter vectors were constructed with different ARE consensus sequences in promoters linked to either fluorescence or luciferase reporter genes in lentiviral vector backbones. Cell lines transduced with the different vectors expressed the reporters in an androgen-dependent way according to fluorescence microscopy, flow cytometry and multi-well fluorescent and luminescence assays. Interestingly, the background reporter activity in androgen-depleted medium was significantly higher in LNCaP cells compared to the prostate transit amplifying epithelial cell lines, EP156T-AR and 957E/hTERT-AR with exogenous AR. The androgen-induced signal to background was much higher in the latter benign prostate cells than in LNCaP cells. Androgen-independent nuclear localization of AR was seen in LNCaP cells and reduced ARE-signaling was seen following treatment with abiraterone, an androgen synthesis inhibitor. The ARE reporter activity was significantly stronger when stimulated by androgens than by β-estradiol, progesterone and dexamethasone in all tested cell types. Finally, no androgen-induced ARE reporter activity was observed in tumorigenic mesenchymal progeny cells of EP156T cells following epithelial to mesenchymal transition. This underscores the observation that expression of the classical luminal differentiation transcriptome is restricted in mesenchymal type cells with or without AR expression, and presence of androgen.

show abstract

Generation of Prostate Tumor–Initiating Cells Is Associated with Elevation of Reactive Oxygen Species and IL-6/STAT3 Signaling

Cited by 70 publications

References 41 publications

Omani propolis: chemical profiling, antibacterial activity and new propolis plant sources

Omani propolis: chemical profiling, antibacterial activity and new propolis plant sources

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

An androgen response element driven reporter assay for the detection of androgen receptor activity in prostate cells

Contact Info

Product

Resources

About