scholarly journals Tanshinone IIA affects the malignant growth of Cholangiocarcinoma cells by inhibiting the PI3K-Akt-mTOR pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Huayuan Liu ◽  
Caiyun Liu ◽  
Mengya Wang ◽  
Dongxu Sun ◽  
Pengcheng Zhu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Protein Protein Interactions ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Cholangiocarcinoma Cell ◽  
And Migration ◽  
Proliferation And Migration

AbstractIn the present study, we aimed to find the target of Tanshinone IIA (Tan-IIA) in Cholangiocarcinoma by network pharmacology-based prediction and investigate the possible mechanism through experimental verification. In this study, we combined Tan-IIA-specific and Cholangiocarcinoma-specific targets with protein–protein interactions (PPI) to construct a Tan-IIA targets-Cholangiocarcinoma network, and network pharmacology approach was applied to identify potential targets and mechanisms of Tan-IIA in the treatment of Cholangiocarcinoma. The anti-cancer effects of Tan-IIA were investigated by using subcutaneous tumorigenic model in nude mice and in the human Cholangiocarcinoma cell lines in vitro. Our results showed that Tan-IIA treatment considerably suppressed the proliferation and migration of Cholangiocarcinoma cells while inducing apoptosis of Cholangiocarcinoma cells. Western blot results demonstrated that the expression of PI3K, p-Akt, p-mTOR, and mTOR were inhibited by Tan-IIA. Meanwhile, After treatment with Tan-IIA, the level of Bcl2 was downregulated and cleaved caspase-3 expression increased. Further studies revealed that the anticancer effects of Tan-IIA were severely mitigated by pretreatment with a PI3K agonist. Our research provides a new anticancer strategy and strengthens support for the use of Tan-IIA as an anticancer drug for the treatment of CCA.

scholarly journals Tanshinone IIA Affects the Malignant Growth of Cholangiocarcinoma Cells by Inhibiting the PI3K-Akt-mTOR Pathway

2021 ◽  
Author(s):  
Huayuan Liu ◽  
Caiyun Liu ◽  
Mengya Wang ◽  
Dongxu Sun ◽  
Pengcheng Zhu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Protein Protein Interactions ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Cholangiocarcinoma Cell ◽  
And Migration ◽  
Proliferation And Migration

Abstract Purpose: In the present study, we aimed to find the target of Tanshinone IIA (Tan-IIA) in Cholangiocarcinoma by network pharmacology-based prediction and investigate the possible mechanism through experimental verification. Methods: In this study, we combined Tan-IIA-specific and Cholangiocarcinoma-specific targets with protein-protein interactions (PPI) to construct a Tan-IIA targets-Cholangiocarcinoma network, and network pharmacology approach was applied to identify potential targets and mechanisms of Tan-IIA in the treatment of Cholangiocarcinoma. The anti-cancer effects of Tan-IIA were investigated by using subcutaneous tumorigenic model in nude mice and in the human Cholangiocarcinoma cell lines in vitro. Results: Our results showed that Tan-IIA treatment considerably suppressed the proliferation and migration of Cholangiocarcinoma cells while inducing apoptosis of Cholangiocarcinoma cells. Western blot results demonstrated that the expression of PI3K, p-Akt, p-mTOR, and mTOR were inhibited by Tan-IIA. Meanwhile, After treatment with Tan-IIA, the level of Bcl2 was downregulated and cleaved caspase-3 expression increased. Further studies revealed that the anticancer effects of Tan-IIA were severely mitigated by pretreatment with a PI3K agonist.Conclusion: Our research provides a new anticancer strategy and strengthens support for the use of Tan-IIA as an anticancer drug for the treatment of CCA.

Disruption of protein–protein interactions: hot spot detection, structure-based virtual screening and in vitro testing for the anti-cancer drug target – survivin

RSC Advances ◽  
2016 ◽  
Vol 6 (38) ◽  
pp. 31947-31959 ◽  
Author(s):  
Sailu Sarvagalla ◽  
Chun Hei Antonio Cheung ◽  
Ju-Ya Tsai ◽  
Hsing Pang Hsieh ◽  
Mohane Selvaraj Coumar
Keyword(s):  
Protein Interactions ◽  
Drug Target ◽  
Hot Spot ◽  
Cancer Drug ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Spot Detection ◽  
Anti Cancer ◽  
Interaction Interface

Hot spot detection at the protein–protein interaction interface using computational tools helped to identify indinavir as survivin inhibitor.

scholarly journals Curcumin Analogue CA15 Exhibits Anticancer Effects on HEp-2 Cells via Targeting NF-κB

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Jian Chen ◽  
Linlin Zhang ◽  
Yilai Shu ◽  
Liping Chen ◽  
Min Zhu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Laryngeal Cancer ◽  
Clinical Settings ◽  
Migration Flow ◽  
Curcumin Analogue ◽  
Hepatic Cells ◽  
Anticancer Effects ◽  
And Migration ◽  
Proliferation And Migration

Laryngeal carcinoma remains one of the most common malignancies, and curcumin has been proven to be effective against head and neck cancers in vitro. However, it has not yet been applied in clinical settings due to its low stability. In the current study, we synthesized 34 monocarbonyl analogues of curcumin with stable structures. CA15, which exhibited a stronger inhibited effect on laryngeal cancer cells HEp-2 but a lower toxicity on hepatic cells HL-7702 in MTT assay, was selected for further analysis. The effects of CA15 on cell viability, proliferation, migration, apoptosis, and NF-κB activation were measured using MTT, Transwell migration, flow cytometry, Western blot, and immunofluorescence assays in HEp-2 cells. An NF-κB inhibitor, BMS-345541, as well as curcumin was also tested. Results showed that CA15 induced decreased toxicity towards HL-7702 cells compared to curcumin and BMS-345541. However, similar to BMS-345541 and curcumin, CA15 not only significantly inhibited proliferation and migration and induced caspase-3-dependent apoptosis but also attenuated TNF-α-induced NF-κB activation in HEp-2 cells. These results demonstrated that curcumin analogue CA15 exhibited anticancer effects on laryngeal cancer cells via targeting of NF-κB.

Probing the 14-3-3 Isoform-Specificity Profile of Interactions Stabilized by Fusicoccin A

2020 ◽  
Author(s):  
James Frederich ◽  
Ananya Sengupta ◽  
Josue Liriano ◽  
Ewa A. Bienkiewicz ◽  
Brian G. Miller
Keyword(s):  
Protein Interactions ◽  
Neurological Diseases ◽  
Adapter Proteins ◽  
Protein Protein Interactions ◽  
Specific Expression ◽  
Individual Client ◽  
Isoform Specificity ◽  
Fusicoccin A

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. In recent years, FC has emerged as an important chemical probe of human 14-3-3 PPIs implicated in cancer and neurological diseases. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of different 14-3-3 isoforms on FC activity has not been systematically explored. This is a relevant question for the continued development of FC variants because there are seven distinct isoforms of 14-3-3 in humans. Despite their remarkable sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions <i>in vivo</i>. Herein, we report the isoform-specificity profile of FC <i>in vitro</i>using recombinant human 14-3-3 isoforms and a focused library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal 14-3-3 recognition domains of client phosphoproteins targeted by FC in cell culture. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3s. Together, these data provide strong motivation for the development of non-natural FC variants with enhanced selectivity for individual 14-3-3 isoforms.

scholarly journals Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jianye Xu ◽  
Jian Zhang ◽  
Zongpu Zhang ◽  
Zijie Gao ◽  
Yanhua Qi ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Autophagy Induction ◽  
Antitumor Immunotherapy ◽  
Novel Biomarkers ◽  
And Migration ◽  
Immunosuppressive Microenvironment ◽  
Proliferation And Migration ◽  
Glioma Progression

AbstractExosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

scholarly journals Cyr61 promotes Schwann cell proliferation and migration via αvβ3 integrin

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenghui Cheng ◽  
Yawen Zhang ◽  
Yinchao Tian ◽  
Yuhan Chen ◽  
Fei Ding ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Peripheral Nerves ◽  
Molecular Mechanisms ◽  
Αvβ3 Integrin ◽  
Promoting Effect ◽  
Ccn Family ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background Schwann cells (SCs) play a crucial role in the repair of peripheral nerves. This is due to their ability to proliferate, migrate, and provide trophic support to axon regrowth. During peripheral nerve injury, SCs de-differentiate and reprogram to gain the ability to repair nerves. Cysteine-rich 61 (Cyr61/CCN1) is a member of the CCN family of matrix cell proteins and have been reported to be abundant in the secretome of repair mediating SCs. In this study we investigate the function of Cyr61 in SCs. Results We observed Cyr61 was expressed both in vivo and in vitro. The promoting effect of Cyr61 on SC proliferation and migration was through autocrine and paracrine mechanisms. SCs expressed αvβ3 integrin and the effect of Cyr61 on SC proliferation and migration could be blocked via αvβ3 integrin. Cyr61 could influence c-Jun protein expression in cultured SCs. Conclusions In this study, we found that Cyr61 promotes SC proliferation and migration via αvβ3 integrin and regulates c-Jun expression. Our study contributes to the understanding of cellular and molecular mechanisms underlying SC’s function during nerve injury, and thus, may facilitate the regeneration of peripheral nerves after injury.

scholarly journals Identification and Biochemical Characterization of High Mobility Group Protein 20A as a Novel Ca2+/S100A6 Target

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 510
Author(s):  
Maho Yamamoto ◽  
Rina Kondo ◽  
Haruka Hozumi ◽  
Seita Doi ◽  
Miwako Denda ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Biochemical Characterization ◽  
S100 Protein ◽  
High Mobility ◽  
Dependent Manner ◽  
Protein Signaling ◽  
Protein Protein Interactions ◽  
High Mobility Group Protein ◽  
Pulldown Assay

During screening of protein-protein interactions, using human protein arrays carrying 19,676 recombinant glutathione s-transferase (GST)-fused human proteins, we identified the high-mobility protein group 20A (HMG20A) as a novel S100A6 binding partner. We confirmed the Ca2+-dependent interaction of HMG20A with S100A6 by the protein array method, biotinylated S100A6 overlay, and GST-pulldown assay in vitro and in transfected COS-7 cells. Co-immunoprecipitation of S100A6 with HMG20A from HeLa cells in a Ca2+-dependent manner revealed the physiological relevance of the S100A6/HMG20A interaction. In addition, HMG20A has the ability to interact with S100A1, S100A2, and S100B in a Ca2+-dependent manner, but not with S100A4, A11, A12, and calmodulin. S100A6 binding experiments using various HMG20A mutants revealed that Ca2+/S100A6 interacts with the C-terminal region (residues 311–342) of HMG20A with stoichiometric binding (HMG20A:S100A6 dimer = 1:1). This was confirmed by the fact that a GST-HMG20A mutant lacking the S100A6 binding region (residues 311–347, HMG20A-ΔC) failed to interact with endogenous S100A6 in transfected COS-7 cells, unlike wild-type HMG20A. Taken together, these results identify, for the first time, HMG20A as a target of Ca2+/S100 proteins, and may suggest a novel linkage between Ca2+/S100 protein signaling and HMG20A function, including in the regulation of neural differentiation.

scholarly journals Effect of Slit/Robo signaling on regeneration in lung emphysema

2021 ◽  
Author(s):  
Jin-Soo Park ◽  
RyeonJin Cho ◽  
Eun-Young Kang ◽  
Yeon-Mok Oh
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Irreversible Damage ◽  
Lung Epithelial ◽  
And Migration ◽  
Proliferation And Migration

AbstractEmphysema, a pathological component of chronic obstructive pulmonary disease, causes irreversible damage to the lung. Previous studies have shown that Slit plays essential roles in cell proliferation, angiogenesis, and organ development. In this study, we evaluated the effect of Slit2 on the proliferation and migration of mouse lung epithelial cells and its role in regeneration in an emphysema lung mouse model. Here, we have shown that Slit2/Robo signaling contributes to the regeneration of lungs damaged by emphysema. Mouse epithelial lung cells treated with Slit2 exhibited increased proliferation and migration in vitro. Our results also showed that Slit2 administration improved alveolar regeneration in the emphysema mouse model in vivo. Furthermore, Slit2/Robo signaling increased the phosphorylation of ERK and Akt, which was mediated by Ras activity. These Slit2-mediated cellular signaling processes may be involved in the proliferation and migration of mouse lung epithelial cells and are also associated with the potential mechanism of lung regeneration. Our findings suggest that Slit2 administration may be beneficial for alveolar regeneration in lungs damaged by emphysema.

scholarly journals Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro

2021 ◽  
Vol 22 (9) ◽  
pp. 4297
Author(s):  
Matthew Thomas Ferreira ◽  
Juliano Andreoli Miyake ◽  
Renata Nascimento Gomes ◽  
Fábio Feitoza ◽  
Pollyana Bulgarelli Stevannato ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Biology ◽  
Gelatin Zymography ◽  
Viable Cell ◽  
Cell Counting ◽  
Gelatinolytic Activity ◽  
Ep4 Receptor ◽  
And Migration ◽  
Proliferation And Migration

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

scholarly journals Targeting mTOR-CCL20 Signaling May Improve Response to Docetaxel in Head and Neck Squamous Cell Carcinoma

2021 ◽  
Vol 22 (6) ◽  
pp. 3046
Author(s):  
Ming-Huei Chou ◽  
Hui-Ching Chuang ◽  
Yu-Tsai Lin ◽  
Ming-Hsien Tsai ◽  
Ying-Hsien Kao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Cell Growth ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Hnscc Cell ◽  
Proliferation And Migration

Patients with advanced head and neck squamous cell carcinoma (HNSCC) usually show a dismal prognosis. It is this worthwhile to develop new, effective therapeutic regimens for these patients, such as molecular targeted therapy, which is promising as an alternative or combination treatment for HNSCC. The mammalian target of rapamycin (mTOR) pathway, which plays an important role in the carcinogenesis of HNSCC, is the most frequently activated, and is thus worthy of further investigation. In this study, two human HNSCC cell lines, FaDu and SAS, were evaluated for cell growth with trypan blue staining and tumor growth using an orthotopic xenograft model. The immunohistochemical expression of mTOR in the subcutaneous xenograft model and the inhibitory effects of docetaxel on the growth and state of activation of the PI3K/mTOR pathway were also evaluated and examined by colony formation and Western blot, respectively. Cell proliferation and migration were measured by water-soluble tetrazolium salt (WST-1) and OrisTM cell migration assay, respectively. Furthermore, the effects of rapamycin and BEZ235, a phosphatidylinositol 3-kinases (PI3K) and mTOR inhibitor in combination with docetaxel or CCL20 were evaluated in the FaDu and SAS cells. The results showed that the expression of mTOR was significantly higher in the SAS and FaDu xenograft models than in the control. Docetaxel treatment significantly suppressed HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. Additionally, when administered in a dose-dependent fashion, mTOR inhibitors inhibited the growth and migration of the HNSCC cells. This combination was synergistic with docetaxel, resulting in almost complete cell growth and migration arrest. In conclusion, docetaxel significantly inhibited HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. The synergistic and additive activity of mTOR inhibitors combined with docetaxel shows potential as a new treatment strategy for HNSCC.

Sign in / Sign up

Export Citation Format

Share Document