RESUMO
Reactive oxygen species (ROS) produced by endothelial cells and macrophages play important roles in atherogenesis because they promote the formation of oxidized low-density lipoproteins (oxLDL). Extracellular-superoxide dismutase (EC-SOD) is mainly produced by vascular smooth muscle cells (VSMCs), is secreted into the extracellular space, and protects cells from the damaging effects of the superoxide anion. Thus, the expression of EC-SOD in VSMCs is crucial for protecting cells against atherogenesis; however, oxLDL-induced changes in the expression of EC-SOD in VSMCs have not yet been examined. We herein showed that oxLDL decreased EC-SOD mRNA and protein levels by binding to lectin-like oxidized LDL receptor-1 (LOX-1). Moreover, we demonstrated the significant role of mitogen-activated protein kinase (MEK)/extracellular-regulated protein kinase (ERK) signaling in oxLDL-elicited reductions in the expression of EC-SOD and proliferation of VSMCs. The results obtained with the FCS treatment indicate that oxLDL-elicited reductions in the expression of EC-SOD are related to the proliferation of VSMCs. We herein showed for the first time that luteolin, a natural product, restored oxLDL-induced decreases in the expression of EC-SOD and proliferation of VSMCs. Collectively, the results of the present study suggest that oxLDL accelerates the development of atherosclerosis by suppressing the expression of EC-SOD and also that luteolin has potential as a treatment for atherosclerosis. J. Cell. Biochem. 117: 2496-2505, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Proliferação de Células/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Receptores Depuradores Classe E/metabolismo , Superóxido Dismutase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Western Blotting , Células Cultivadas , Humanos , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Depuradores Classe E/genética , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
mTOR complex 2 (mTORC2) signaling is upregulated in multiple types of human cancer, but the molecular mechanisms underlying its activation and regulation remain elusive. Here, we show that microRNA-mediated upregulation of Rictor, an mTORC2-specific component, contributes to tumor progression. Rictor is upregulated via the repression of the miR-424/503 cluster in human prostate and colon cancer cell lines that harbor c-Src upregulation and in Src-transformed cells. The tumorigenicity and invasive activity of these cells were suppressed by re-expression of miR-424/503. Rictor upregulation promotes formation of mTORC2 and induces activation of mTORC2, resulting in promotion of tumor growth and invasion. Furthermore, downregulation of miR-424/503 is associated with Rictor upregulation in colon cancer tissues. These findings suggest that the miR-424/503-Rictor pathway plays a crucial role in tumor progression.
