The novel role and underlying mechanism of Wnt5a in regulating cellular cholesterol accumulation. Qin Li,Hu Rong,Zhu Neng,Yao Hai-Lun,Lei Xiao-Yong,Li Shun-Xiang,Liao Duan-Fang,Zheng Xi-Long Clinical and experimental pharmacology & physiology Cholesterol accumulation is a critical step during the development and progression of atherosclerosis. Recently, Wnt5a expression has been found to be markedly upregulated in both murine and human atherosclerotic lesions. However, the effect and mechanism of Wnt5a in atherosclerosis is poorly understood. In the present study, we investigated the effects and potential mechanisms of Wnt5a on cholesterol accumulation during atherosclerosis. We used RAW264.7 and vascular smooth muscle cells (VSMC) treated with oxidized low-density lipoprotein (oxLDL) as lipid-loaded cell models. We found that expression of Wnt5a protein was increased in a concentration (25, 50, 75 and 100 μg/mL)- and time (24, 48 and 72 h)-dependent manner by oxLDL treatment. To explore the underlying mechanism, we used Wnt5a short interference (si) RNA to knockdown Wnt5a expression in both RAW264.7 cells and VSMC, or applied recombinant Wnt5a (rWnt5a) to stimulate Wnt5a signalling. After Wnt5a knockdown, total cholesterol (TC) and free cholesterol (FC) content in both cell types increased significantly (P < 0.05) upon exposure to oxLDL. Conversely, the TC and FC content decreased markedly (P < 0.05) after treatment of cells with rWnt5a. More importantly, both protein and mRNA expression of Caveolin-1 and ATP-binding cassette transporter A1 (ABCA1) was significantly reduced after exposure of wnt5a siRNA-treated cells to oxLDL, whereas rWnt5a treatment of cells resulted in increased Caveolin-1 and ABCA1 protein expression after exposure of cells to oxLDL. Together, these findings demonstrate, for the first time, that Wnt5a reduces the accumulation of cholesterol in lipid-loaded cells by regulating the mRNA expression of Caveolin-1 and ABCA1, which are involved in reverse cholesterol transport. This may present a novel mechanism of Wnt5a-mediated cholesterol transportation in macrophages and VSMC. Therefore, targeting the Wnt5a signalling pathway may have clinical implications in atherosclerosis. 10.1111/1440-1681.12258

Tyrosine-phosphorylated caveolin-1 (Tyr-14) increases sensitivity to paclitaxel by inhibiting BCL2 and BCLxL proteins via c-Jun N-terminal kinase (JNK). Shajahan Ayesha N,Dobbin Zachary C,Hickman F Edward,Dakshanamurthy Sivanesan,Clarke Robert The Journal of biological chemistry Paclitaxel, an anti-microtubule agent, is an effective chemotherapeutic drug in breast cancer. Nonetheless, resistance to paclitaxel remains a major clinical challenge. The need to better understand the resistant phenotype and to find biomarkers that could predict tumor response to paclitaxel is evident. In estrogen receptor α-positive (ER(+)) breast cancer cells, phosphorylation of caveolin-1 (CAV1) on Tyr-14 facilitates mitochondrial apoptosis by increasing BCL2 phosphorylation in response to low dose paclitaxel (10 nM). However, two variants of CAV1 exist: the full-length form, CAV1α (wild-type CAV1 or wtCAV1), and a truncated form, CAV1β. Only wtCAV1 has the Tyr-14 region at the N terminus. The precise cellular functions of CAV1 variants are unknown. We now show that CAV1 variants play distinct roles in paclitaxel-mediated cell death/survival. CAV1β expression is increased in paclitaxel-resistant cells when compared with sensitive cells. Expression of CAV1β in sensitive cells significantly reduces their responsiveness to paclitaxel. These activities reflect an essential role for Tyr-14 phosphorylation because wtCAV1 expression, but not a phosphorylation-deficient mutant (Y14F), inactivates BCL2 and BCLxL through activation of c-Jun N-terminal kinase (JNK). MCF-7 cells that express Y14F are resistant to paclitaxel and are resensitized by co-treatment with ABT-737, a BH3-mimetic small molecule inhibitor. Using structural homology modeling, we propose that phosphorylation on Tyr-14 enables a favorable conformation for proteins to bind to the CAV1 scaffolding domain. Thus, we highlight novel roles for CAV1 variants in cell death; wtCAV1 promotes cell death, whereas CAV1β promotes cell survival by preventing inactivation of BCL2 and BCLxL via JNK in paclitaxel-mediated apoptosis. 10.1074/jbc.M111.304022

Noncanonical Wnt as a prognostic marker in prostate cancer: "you can't always get what you Wnt". Fisher Rebecca R,Pleskow Haley M,Bedingfield Kathleen,Miyamoto David T Expert review of molecular diagnostics : Wnt signaling is important for normal development, cell proliferation, and cell differentiation. However, aberrations in the pathway can lead to tumorigenesis and cancer progression. Recent genome-wide studies have demonstrated the frequent occurrence of Wnt pathway alterations in prostate cancer. Although alterations in the Wnt pathway in prostate cancer may have an impact on prognosis, recent studies suggest that the Wnt pathway also plays an important role in disease progression and treatment resistance.: We review the literature with regard to the potential prognostic significance of noncanonical Wnt signaling in prostate cancer. After a brief overview of the canonical and noncanonical Wnt pathways, we discuss the preclinical and clinical evidence for activation of Wnt signaling in prostate cancer. We focus on clinical evidence for noncanonical Wnt pathway components to serve as potential prognostic biomarkers.: Although many therapeutic options are available for men with prostate cancer, there remains an unmet need for prognostic and predictive biomarkers to precisely guide clinical management. Early evidence suggests that components of the noncanonical Wnt pathway may serve as prognostic biomarkers. However, prospective validation studies are necessary before these biomarkers can be routinely applied in the clinic. 10.1080/14737159.2020.1702522

The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs. Li Weiwei,Li Yanshu,Zhao Yi,Ren Lina Artificial cells, nanomedicine, and biotechnology Atherosclerosis is a potentially life-threatening cardiovascular disease characterized by chronic endothelial inflammation and the formation of atherosclerotic lesions. Circulating ox-LDL is known to induce atherosclerosis by triggering oxidative stress, the expression of inflammatory mediators and adhesion molecules, as well as downregulating the atheroprotective transcriptional factor KLF2. Aloperine is an alkaloid compound isolated from the plant . Here, we employed various experimental methods to determine the effects of aloperine on ox-LDL-induced markers of atherosclerosis. DHE staining revealed that aloperine may restore the oxidant/antioxidant balance in HUVECs by reducing the level of ROS and rescuing the reduction in NOQ-1 and GCLC induced by ox-LDL. Aloperine treatment reduced ox-LDL-induced expression of IL-6, MCP-1, VCAM-1, and E-selectin and rescued the reduction in KLF2. Aloperine also downregulated ox-LDL-induced expression of the LOX-1. We also demonstrate that aloperine improved cell viability and inhibited the adhesion of U937 monocytes to HUVECs. Finally, we demonstrate that the effects of aloperine are mediated through the rescue of KLF2 expression suppression of the phosphorylation of p53 protein. Together, our results implicate the potential of aloperine as a safe and effective antiatherosclerosis treatment. 10.1080/21691401.2019.1699816

Oxidized low-density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR-496 expression and inhibiting the Hippo pathway effector YAP. Hu Jun,Liu Te,Zhang Zhuang,Xu Yawei,Zhu Fu Cell biology international Oxidized low-density lipoprotein (ox-LDL) can damage vascular endothelial cells and cause atherosclerosis, but its epigenetic regulatory mechanism has not been fully elucidated. We show that ox-LDL induced significant apoptosis and loss of function in human umbilical vascular endothelial cells (HUVECs). At the same time, ox-LDL significantly decreased the expression of Hippo-YAP/ZAP (Yes-associated protein/YLP motif-containing 1) pathway proteins as compared to that of the control. The luciferase reporter system confirmed that microRNA (miR)-496 silenced YAP gene expression by binding to its 3' untranslated region (3' UTR). Ox-LDL-treated miR-496 overexpression HUVECs had a higher apoptosis rate and more severe dysfunction compared to the control cells. This in-depth study shows that ox-LDL inhibits YAP protein expression by inducing miR-496 expression, leading to its inability to enter the nucleus, thereby losing its function as a transcriptional cofactor for activating the downstream genes. Our findings reveal that, through epigenetic modification, ox-LDL can inhibit the normal expression of Hippo-YAP/ZAP pathway proteins via miR-496 expression and induce vascular endothelial cell dysfunction. 10.1002/cbin.11120