Bizzarri Mariano, Dinicola Simona, Bevilacqua Arturo, Cucina Alessandra
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; Systems Biology Group Lab, Sapienza University of Rome, Rome, Italy.
Department of Clinical and Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy.
Int J Endocrinol. 2016;2016:5616807. doi: 10.1155/2016/5616807. Epub 2016 Oct 4.
Inositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, -catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture.
肌醇（肌醇和肌醇六磷酸）在生理和病理环境中发挥着广泛的关键作用。在包括癌症在内的多种疾病中都记录到了肌醇代谢失调的情况，在癌症中肌醇可调节不同的关键通路。肌醇抑制pRB磷酸化，促进pRB/E2F复合物的形成，并阻断细胞周期进程。肌醇降低PI3K水平，从而抵消PI3K激活下游的PKC/RAS/ERK通路的激活。在该通路的上游，肌醇破坏FGF与其受体之间的配体相互作用以及涉及IGF-II受体和AP-1复合物的EGF转导过程。此外，添加肌醇后Akt激活受到严重损害。Akt和ERK的下调进而导致NF-κB抑制以及炎症标志物（COX-2和PGE2）表达降低。值得注意的是，肌醇诱导的早老素-1下调会干扰上皮-间质转化，并减少Wnt激活、β-连环蛋白易位、Notch-1、N-钙黏蛋白和SNAI1释放。肌醇还通过上调黏着斑激酶和E-钙黏蛋白以及降低丝状肌动蛋白和丝切蛋白（伪足的两个主要成分）来干扰细胞骨架，从而导致侵袭能力受损。肌醇对金属蛋白酶和ROCK1/2释放的抑制作用进一步增强了这种效果。总体而言，这些作用使肌醇能够重塑细胞骨架结构。
