Anti-inflammatory effects of nobiletin on TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in prostate cancer cells

Özkan, Asuman Deveci; Kaleli, Süleyman; Onen, Hacer Ilke; Sarıhan, Mehmet; Eskiler, Gamze Güney; Yiğin, Aysel Kalaycı; Akdoğan, Mehmet

doi:10.1080/08923973.2020.1725040

Cited by 33 publications

(16 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that nobiletin inhibits the growth of prostate cancer cells by suppressing TLR4/TRIF/IRF3, TLR9/IRF7 [ 43 ] and AKT [ 44 ] signaling pathways. In our current study, we observed that nobiletin caused the inhibition of the cell viability of prostate cancer cells, especially AR/AR-V7-positive cells.…”

Section: Discussionmentioning

confidence: 99%

Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Liu

Shao

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

Androgen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Liu

Shao

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…PC-3 was cultured in RPMI-1640 (Thermo Fisher, USA) and HUVEC cells were grown in DMEM medium (Thermo Fisher, USA) supplemented with 0.1% penicillin and streptomycin, 10% FBS, and incubated at 37°C with 5% CO2. The optimal treatment concentration and times for NOB in PC-3 and HUVEC cell lines were determined in our previous studies (Deveci Ozkan et al, 2020). Therefore, all cells were treated with NOB (80 µM for PC-3 and HUVEC, respectively) for 48 h in all experiments.…”

Section: Cell Culture and Nob Treatmentmentioning

confidence: 99%

“…NOB is antiapoptotic, anti-inflammatory, anti-tumor, and antioxidant and an effective inhibitor against human prostate cancer cells and melanoma cells (Kunimasa et al, 2010;Lee et al, 2013;Xiao et al, 2016;Huang et al, 2016;Surichana et al, 2018). Additionally, studies have shown that NOB has an anti-inflammatory effect and exhibit an inhibiting effect on tumor invasion, proliferation, and metastasis and inhibit the creation of reactive oxygen species (ROS) by increasing the superoxide dismutase (SOD) and glutathione (GSH) activity and reduction in the making of malondialdehyde (MDA) and H2O2-induced PC12 cells (Luo et al, 2008;Lu et al, 2010;Güney Eskiler et al;Liu et al, 2019;Deveci Ozkan et al, 2020). In addition, researchers reported that nobiletin impeded cell proliferation both depending on the dose and duration and prevented cell cycle progression in G1 (Morley et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Role of Citrus Nobiletin on Oxidative Stress Levels and Superoxide Dismutase Activities in Metastatic Castration-Resistant Prostate Cancer

Yüksel¹,

Özkan²

2021

Commagene Journal of Biology

View full text Add to dashboard Cite

Nobiletin (NOB) is a polymethoxylated flavone. It has multiple biologic activities that can modulate oxidative stress in many cancer types. However, there is no study in the literature that has examined the effects of NOB on oxidative stress levels in Metastatic Castration-Resistant Prostate Cancer (MCRPC) yet. Motivated from this gap, we investigated the impact of NOB on oxidative stress and superoxide dismutase (SOD) enzyme activities in MCRPC as a preliminary study. For this purpose, PC-3 and HUVEC cells were used to determine the effects of NOB on the amount of Malondialdehyde (MDA), hydrogen peroxide (H2O2), and proline as well as SOD enzyme activities. NOB potentially induced SOD enzyme activities but the level of MDA, H2O2, and proline decreased after incubation with NOB in PC-3 cells (p<.05 and p<.001 were considered statistically significant). Our results confirmed that NOB acted as a protective agent for cancer cells and could selectively regulate oxidant status in MCRPC cells. Consequently, these preliminary findings provide better insight into the role of citrus NOB on oxidative stress levels and antioxidant enzyme activities in MCRPC. Additionally, there is a need to elucidate the molecular mechanisms of this cytoprotective effect of NOB as a potential chemotherapeutic agent.

show abstract

“…Endoplasmic reticulum‐localized Htd1 improved inflammation through TLR4 during bacterial infection (Lu et al., 2019). Moreover, TLR4 is implicated in the pathophysiology of inflammation‐related diseases, such as cardiovascular diseases, diabetes, cancer (Bai et al., 2019; Balistreri et al., 2009; Deveci Ozkan et al., 2020; Huang et al., 2017; Shetab Boushehri & Lamprecht, 2018; Stoll et al., 2006; Yang et al., 2019). TLR4 involves in the inflammatory cytokines storm, eventually leading to the development and progression of inflammation‐based septic shock.…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor 4 antagonist FP7 alleviates lipopolysaccharide‐induced septic shock via NF‐kB signaling pathway

Wang

Zhao

et al. 2021

Chem Biol Drug Des

View full text Add to dashboard Cite

Septic shock is the most severe complication of sepsis occurs when body has an overwhelming response to infection, making it the most prevalent cause of deaths in surgical intensive‐care units. Therefore, it is urgent to understand its pathogenesis and develop new therapeutic candidate drugs for septic shock. Here, we explored the effect of FP7, an antagonist of Toll‐like receptor 4 (TLR4), in the septic shock. First, we injected mice with FP7 and found that FP7 had no effect on immune cells. Then, bone marrow‐derived macrophages (BMDMs) isolated from mice were pretreated with FP7 followed by lipopolysaccharide (LPS) stimulation, and FP7 specifically suppressed LPS‐induced inflammatory responses in BMDMs via Nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐κB) signaling pathway, with no effect on other TLRs‐mediated inflammations. Finally, we injected mice with LPS and D‐galactosamine to induce septic shock, followed by the treatment of FP7, and FP7 significantly increased survival rate, improved lung necrosis, and inhibited the secretions of proinflammatory cytokines in the mice with septic shock. Therefore, our study suggested that FP7 had a protective role in septic shock and it might serve as a promising therapeutic candidate drug to treat septic shock.

show abstract

Anti-inflammatory effects of nobiletin on TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in prostate cancer cells

Cited by 33 publications

References 36 publications

Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

The Role of Citrus Nobiletin on Oxidative Stress Levels and Superoxide Dismutase Activities in Metastatic Castration-Resistant Prostate Cancer

Toll‐like receptor 4 antagonist FP7 alleviates lipopolysaccharide‐induced septic shock via NF‐kB signaling pathway

Contact Info

Product

Resources

About