scholarly journals aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2–mediated SphK1-S1PR1-Akt signaling axis

2021 ◽  
Vol 118 (49) ◽  
pp. e2106623118
Author(s):  
Olivia Molinar-Inglis ◽  
Cierra A. Birch ◽  
Dequina Nicholas ◽  
Lennis Orduña-Castillo ◽  
Metztli Cisneros-Aguirre ◽  
...  
Keyword(s):  
Cell Death ◽  
Endothelial Dysfunction ◽  
Signaling Pathways ◽  
Activated Protein C ◽  
Akt Signaling ◽  
Endothelial Barrier ◽  
Structural Protein ◽  
Signaling Axis ◽  
Sphingosine 1 Phosphate ◽  
Apoptotic Activity

Endothelial dysfunction is associated with vascular disease and results in disruption of endothelial barrier function and increased sensitivity to apoptosis. Currently, there are limited treatments for improving endothelial dysfunction. Activated protein C (aPC), a promising therapeutic, signals via protease-activated receptor-1 (PAR1) and mediates several cytoprotective responses, including endothelial barrier stabilization and anti-apoptotic responses. We showed that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to promote Rac1 activation and barrier protection. However, the signaling pathways utilized by aPC/PAR1 to mediate anti-apoptotic activities are not known. aPC/PAR1 cytoprotective responses also require coreceptors; however, it is not clear how coreceptors impact different aPC/PAR1 signaling pathways to drive distinct cytoprotective responses. Here, we define a β-arr2–mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. Using human cultured endothelial cells, we found that endogenous PAR1 and S1PR1 coexist in caveolin-1 (Cav1)–rich microdomains and that S1PR1 coassociation with Cav1 is increased by aPC activation of PAR1. Our study further shows that aPC stimulates β-arr2–dependent SphK1 activation independent of Dvl2 and is required for transactivation of S1PR1-Akt signaling and protection against cell death. While aPC/PAR1-induced, extracellular signal–regulated kinase 1/2 (ERK1/2) activation is also dependent on β-arr2, neither SphK1 nor S1PR1 are integrated into the ERK1/2 pathway. Finally, aPC activation of PAR1-β-arr2–mediated protection against apoptosis is dependent on Cav1, the principal structural protein of endothelial caveolae. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete, β-arr2–driven signaling pathways in caveolae.

scholarly journals aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete β-arrestin-2 mediated SphK1-S1PR1-Akt signaling axis

2021 ◽  
Author(s):  
Olivia Molinar-Inglis ◽  
Cierra A. Birch ◽  
Dequina Nicholas ◽  
Metzli Cisneros-Aguirre ◽  
Anand Patwardhan ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Vascular Diseases ◽  
Akt Signaling ◽  
Sphingosine Kinase 1 ◽  
Caveolin 1 ◽  
Signaling Axis ◽  
Sphingosine 1 Phosphate ◽  
Protease Activated Receptor 1 ◽  
Apoptotic Activity

Endothelial dysfunction is associated with multiple vascular diseases and lacks effective treatments. Activated Protein C (aPC) is a promising biotherapeutic that signals via protease-activated receptor-1 (PAR1) to promote diverse cytoprotective responses, including endothelial barrier stabilization, anti-inflammatory and anti-apoptotic activities, which is facilitated by co-receptors. We showed that aPC-activated PAR1 signals preferentially via b-arrestin-2 (b-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to enhance barrier protection. However, the mechanisms by which aPC/PAR1 promotes other cytoprotective responses are poorly understood. Here we define a novel β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. We show that PAR1 and S1PR1 co-exist in caveolin-1-rich microdomains basally and aPC markedly increases S1PR1-caveolin-1 co-association. Moreover, aPC stimulates b-arr2-dependent SphK1 activation independent of Dvl2, which is critical for S1PR1 transactivation. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete b-arr2-driven signaling pathways in caveolae.

Physalin B induces apoptosis in hepatocellular carcinoma through reactive oxygen species activation via TGF-β, NF-κB and PI3K/AKT signaling pathways

2020 ◽  
Vol 10 (4) ◽  
pp. 578-584 ◽  
Author(s):  
Zhendong Zhao ◽  
Guohong Zhou ◽  
Yanjun Yang ◽  
Li Xia ◽  
Dandan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Reactive Oxygen ◽  
Akt Signaling ◽  
Oxygen Species ◽  
The World ◽  
Cellular Reactive Oxygen Species ◽  
Apoptotic Activity

It is acknowledged that hepatocellular carcinoma (HCC) cause the most cancer-associated mortality all around the world and the traditional Chinese medicine has been widely used in HCC treatment. Physalin B (PB) is the most important chemical compounds of a Chinese traditional herb, Physalis alkekengi var. franchetii. In this research, it is the first time in the world that we illustrated PB exhibits obvious apoptotic activity in SMMC-7721 and HepG2 human HCC cell lines in the does-dependent way. Moreover, decrease in mitochondrial membrane potential (MMP) was found and the cellular reactive oxygen species (ROS) was obviously upregulated in PB-treated cell lines. Furthermore, the expression of apoptosis-associated proteins and ROS were increased after the treatment of PB, which were reversed by the inhibitor of TGF-β, NF-κB or PI3K/AKT signaling pathways. Therefore, PB illustrates potent anticancer activity, which might be studied as a potentiation therapeutic medicine for HCC.

scholarly journals Quercetin Induces Apoptosis via Downregulation of Vascular Endothelial Growth Factor/Akt Signaling Pathway in Acute Myeloid Leukemia Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Huan Shi ◽  
Xin-Yu Li ◽  
Yao Chen ◽  
Xing Zhang ◽  
Yong Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Akt Signaling ◽  
Convincing Evidence ◽  
Chemical Proteomics ◽  
Mitochondria Membrane Potential ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive haematological malignancy characterized by highly proliferative accumulation of immature and dysfunctional myeloid cells. Quercetin (Qu), one kind of flavonoid, exhibits anti-cancer property in multiple types of solid tumor, but its effect on acute myeloid leukemia is less studied, and the underlying mechanisms still largely unknown. This study aimed to explore the specific target and potential mechanism of quercetin-induced cell death in AML. First, we found that quercetin induces cell death in the form of apoptosis, which was caspase dependent. Second, we found that quercetin-induced apoptosis depends on the decrease of mitochondria membrane potential (MMP) and Bcl-2 proteins. With quantitative chemical proteomics, we observed the downregulation of VEGFR2 and PI3K/Akt signaling in quercetin-treated cells. Consistently, cell studies also identified that VEGFR2 and PI3K/Akt signaling pathways are involved in the action of quercetin on mitochondria and Bcl-2 proteins. The decrease of MMP and cell death could be rescued when PI3K/Akt signaling is activated, suggesting that VEGFR2 and PI3K/Akt exert as upstream regulators for quercetin effect on apoptosis induction in AML cells. In conclusion, our findings from this study provide convincing evidence that quercetin induces cell death via downregulation of VEGF/Akt signaling pathways and mitochondria-mediated apoptosis in AML cells.

Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways

2015 ◽  
Vol 40 (9) ◽  
pp. 1929-1944 ◽  
Author(s):  
Jiao Hua Jiang ◽  
Guo Ge ◽  
Kai Gao ◽  
Ying Pang ◽  
Rui Chao Chai ◽  
...  
Keyword(s):  
Cell Death ◽  
Calcium Signaling ◽  
Signaling Pathways ◽  
Akt Signaling

Crude extract of Origanum vulgare L. induced cell death and suppressed MAPK and PI3/Akt signaling pathways in SW13 and H295R cell lines

2018 ◽  
Vol 33 (11) ◽  
pp. 1646-1649 ◽  
Author(s):  
Beatrice Rubin ◽  
Jacopo Manso ◽  
Halenya Monticelli ◽  
Loris Bertazza ◽  
Marco Redaelli ◽  
...  
Keyword(s):  
Cell Death ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Crude Extract ◽  
Akt Signaling ◽  
Origanum Vulgare

scholarly journals Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1968-1973 ◽  
Author(s):  
Geerte L. Van Sluis ◽  
Tatjana M.H. Niers ◽  
Charles T. Esmon ◽  
Wikky Tigchelaar ◽  
Dick J. Richel ◽  
...  
Keyword(s):  
Protective Effect ◽  
Cancer Cell ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Vascular Leakage ◽  
Endothelial Barrier ◽  
Blue Dye ◽  
Vascular Endothelial ◽  
Sphingosine 1 Phosphate

Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial barrier through sphingosine-1-phosphate receptor-1 (S1P1)activation, which may counteract cancer cell extravasation. Here, we provide evidence that endogenous APC limits cancer cell extravasation, with in vivo use of monoclonal antibodies against APC. The protective effect of endogenous APC depends on its signaling properties. The MAPC1591 antibody that only blocks anticoagulant activity of APC does not affect cancer cell extravasation as opposed to MPC1609 that blocks anticoagulant and signaling properties of APC. Combined administration of anti-APC antibodies and S1P1 agonist (SEW2871) resulted in a similar number of pulmonary foci in mice in presence and absence of APC, indicating that the protective effect of APC depends on the S1P1 pathway. Moreover, endogenous APC prevents cancer cell–induced vascular leakage as assessed by the Evans Blue Dye assay, and SEW2871 treatment reversed MPC1609-dependent vascular leakage. Finally, we show that cancer cells combined with MPC1609 treatment diminished endothelial VE-cadherin expression. In conclusion, endogenous APC limits cancer cell extravasation because of S1P1-mediated VE-cadherin–dependent vascular barrier enhancement.

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