SUMMARY
BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1-targeted cancer treatment in animals.
E-cadherin (E-cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane-tethered form and a soluble form. Full-length E-cad is membrane tethered. As a type I transmembrane glycoprotein, E-cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E-cad (sE-cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full-length E-cad. The production of sE-cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE-cad can diffuse into the extracellular environment and the blood. As a paracrine/ autocrine signaling molecule, sE-cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE-cad in tumorigenesis and tumor progression and its significance in clinical therapeutics.
DNA is well-documented to stimulate immune response. However, the nature of the DNA to activate immune surveillance is less understood. Here, we show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, which is controlled by DNA-sequence, -damage and -length. Consistently, DNA-sequence was shown to control cGAS activation. Structural analyses revealed that a conserved cGAS residue (mouse R222 or human R236) contributed to the DNA-flexibility detection. And the residue substitution neutralised the flexibility-controlled DNA-potential to activate cGAS, and relaxed the DNA-length specificity of cGAS. Moreover, low dose radiation was shown to mount cGAS-mediated acute immune surveillance (AIS) via repairable (reusable) DNAs in hrs. Loss of cGAS-mediated AIS decreased the regression of local and abscopal tumours in the context of focal radiation and immune checkpoint blockade. Our results build a direct link between immunosurveillance and DNA mechanical feature.
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