Background
The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC).
Objective
Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer.
Methods
Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer.
Results
Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC.
Conclusion
The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.
Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.
Graphical abstract
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