scholarly journals Safrana l Prevents Prostate Cancer Recurrence by Blocking the Re-activation of Quiescent Cancer Cells via Downregulation of S-Phase Kinase-Associated Protein 2

2020 ◽  
Vol 8 ◽  
Author(s):  
Xue Jiang ◽  
Yang Li ◽  
Ji-ling Feng ◽  
Wan Najbah Nik Nabil ◽  
Rong Wu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Transcriptional Activity ◽  
Kinase Inhibitors ◽  
Crocus Sativus ◽  
Akt Phosphorylation

The re-proliferation of quiescent cancer cells is considered to be the primary contributor to prostate cancer (Pca) recurrence and progression. In this study, we investigated the inhibitory effect of safranal, a monoterpene aldehyde isolated from Crocus sativus (saffron), on the re-proliferation of quiescent Pca cells in vitro and in vivo. The results showed that safranal efficiently blocked the re-activation of quiescent Pca cells by downregulating the G0/G1 cell cycle regulatory proteins CDK2, CDK4, CDK6, and phospho-Rb at Ser807/811 and elevating the levels of cyclin-dependent kinase inhibitors, p21 and p27. Further investigation on the underlying mechanisms revealed that safranal suppressed the mRNA and protein expression levels of Skp2, possibly through the deregulation of the transcriptional activity of two major transcriptional factors, E2F1 and NF-κB subunits. Moreover, safranal inhibited AKT phosphorylation at Ser473 and deregulated both canonical and non-canonical NF-κB signaling pathways. Safranal suppressed the tumor growth of quiescent Pca cell xenografts in vivo. Furthermore, safranal-treated tumor tissues exhibited a reduction in Skp2, E2F1, NF-κB p65, p-IκBα (Ser32), c-MYC, p-Rb (Ser807), CDK4, CDK6, and CDK2 and an elevation of p27 and p21 protein levels. Therefore, our findings demonstrate that safranal suppresses cell cycle re-entry of quiescent Pca cells in vitro and in vivo plausibly by repressing the transcriptional activity of two major transcriptional activators of Skp2, namely, E2F1 and NF-κB, through the downregulation of AKT phosphorylation and NF-κB signaling pathways, respectively.

scholarly journals Src acts as the target of matrine to inhibit the proliferation of cancer cells by regulating phosphorylation signaling pathways

2020 ◽  
Author(s):  
Xi Zhang ◽  
Hui Xu ◽  
Xiaoyang Bi ◽  
Guoqing Hou ◽  
Andong Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Kinase Activity ◽  
Src Kinase ◽  
Kinase Domain ◽  
Akt Phosphorylation ◽  
In Vivo Experiments

Background and Purpose: Identification of accurate targets is essential for a successful development of targeted therapy in cancer. Studies have shown that matrine has antitumor activity against many types of cancers. However, the direct target in cancer cells of its anticancer effect has not been identified. The purpose of this study was to find the molecular target of matrine to inhibit the proliferation of cancer cells and explore its mechanism of action. Experimental Approach: The effect of matrine on the proliferation of cancer cells were examined by MTT assay. Pull-down assay and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) were performed to explore the target of matrine. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which matrine targeted Src to regulate the downstream signaling pathways of Src in cancer cells. Key Results: Herein we showed that matrine inhibited the proliferation of cancer in vitro and in vivo. Pull-down assay with matrine-amino coupling resins (MA beads) and LC-MS/MS identified Src as the target of matrine. Src kinase domain is required for its interaction with matrine and Ala392 in the kinase domain participated in matrine-Src interaction. Intriguingly, matrine was proven to inhibit Src kinase activity in a non-ATP-competitive manner by blocking the autophosphorylation of Tyr419. Matrine down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3 and PI3K/Akt signaling pathways. Conclusions and Implications: Collectively, matrine targeted Src, inhibited kinase activity and down-regulated its downstream MAPK/ERK, JAK2/STAT3 and PI3K/Akt phosphorylation signaling pathways to inhibit the proliferation of cancer cells.

scholarly journals KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 748 ◽  
Author(s):  
Juan Li ◽  
Baotong Zhang ◽  
Mingcheng Liu ◽  
Xing Fu ◽  
Xinpei Ci ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
Prostate Cancer Cells ◽  
Normal Prostate ◽  
Promote Cell Proliferation ◽  
Therapeutic Opportunity

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.

scholarly journals Benefits of whole ginger extract in prostate cancer

2011 ◽  
Vol 107 (4) ◽  
pp. 473-484 ◽  
Author(s):  
Prasanthi Karna ◽  
Sharmeen Chagani ◽  
Sushma R. Gundala ◽  
Padmashree C. G. Rida ◽  
Ghazia Asif ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Oral Feeding ◽  
Reproductive Capacity ◽  
Proliferation Index ◽  
Prostate Cancer Cells ◽  
Ginger Extract

It is appreciated far and wide that increased and regular consumption of fruits and vegetables is linked with noteworthy anticancer benefits. Extensively consumed as a spice in foods and beverages worldwide, ginger (Zingiber officinale Roscoe) is an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Ginger has been known to display anti-inflammatory, antioxidant and antiproliferative activities, indicating its promising role as a chemopreventive agent. Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells. Comprehensive studies have confirmed that GE perturbed cell-cycle progression, impaired reproductive capacity, modulated cell-cycle and apoptosis regulatory molecules and induced a caspase-driven, mitochondrially mediated apoptosis in human prostate cancer cells. Remarkably, daily oral feeding of 100 mg/kg body weight of GE inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice, as shown by measurements of tumour volume. Tumour tissue from GE-treated mice showed reduced proliferation index and widespread apoptosis compared with controls, as determined by immunoblotting and immunohistochemical methods. Most importantly, GE did not exert any detectable toxicity in normal, rapidly dividing tissues such as gut and bone marrow. To the best of our knowledge, this is the first report to demonstrate the in vitro and in vivo anticancer activity of whole GE for the management of prostate cancer.

scholarly journals Src acts as the target of matrine to inhibit the proliferation of cancer cells by regulating phosphorylation signaling pathways

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Xi Zhang ◽  
Hui Xu ◽  
Xiaoyang Bi ◽  
Guoqing Hou ◽  
Andong Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Kinase Activity ◽  
Src Kinase ◽  
Kinase Domain ◽  
Akt Phosphorylation ◽  
Cellular Thermal Shift Assay

AbstractStudies have shown that matrine has antitumor activity against many types of cancers. However, the direct target in cancer cells of its anticancer effect has not been identified. The purpose of this study was to find the molecular target of matrine to inhibit the proliferation of cancer cells and explore its mechanism of action. Herein we showed that matrine inhibited the proliferation of cancer in vitro and in vivo. Pull-down assay with matrine-amino coupling resins and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) identified Src as the target of matrine. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) provided solid evidences that matrine directly bound to Src. Bioinformatics prediction and pull-down experiment demonstrated that Src kinase domain was required for its interaction with matrine and Ala392 in the kinase domain participated in matrine–Src interaction. Intriguingly, matrine was proven to inhibit Src kinase activity in a non-ATP-competitive manner by blocking the autophosphorylation of Tyr419 in Src kinase domain. Matrine down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3, and PI3K/Akt signaling pathways via targeting Src. Collectively, matrine targeted Src, inhibited its kinase activity, and down-regulated its downstream MAPK/ERK, JAK2/STAT3, and PI3K/Akt phosphorylation signaling pathways to inhibit the proliferation of cancer cells.

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

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