Research Paper Volume 12, Issue 2 pp 1928—1951

Figure 9. Schematic representation of the proposed action mechanism of DF2755A in modulating the cytoskeletal dynamics. Our study shows the central role of autocrine/paracrine CXCL8 and CXCR1/CXCR2 in activating the cellular mechanisms related to cell motility and cytoskeleton dynamics underlying GB invasiveness. The CXCL8 interaction with CXCR1/CXCR2 triggers the subunits of the heterotrimeric G-protein. The Giα subunit is able to directly induce the Fak phosphorylation at tyrosine 397, which in turn allows Fak-cortactin interaction. This interaction plays a key role in the regulation of cell motility and it is promoted by α-tubulin acetylation. Moreover, Giα can indirectly induce Fak phosphorylation by PI3K/Akt as well as could be involved in YAP/TAZ nuclear translocation. Instead, γ and β subunits can activate RhoA and Cdc42, proteins involved in cytoskeleton rearrangement occurring during cell migration. All GPCR subunits are positively linked to nuclear translocation of NF-κB p65 and IκBβ degradation. Interestingly, CXCR1/CXCR2 could, in some way, to be involved in α-tubulin acetylation on lysine 40, but this hypothetical correlation needs further investigation. DF2755A allosteric inhibitor shows the ability to adversely affect these CXCL8-CXCR1/CXCR2-dependent mechanisms resulting in a reduction of cellular motility. Black lines with arrowheads represent CXCL8-CXCR1/CXCR2-activated signalling pathways. Dashed gray line represents direct activation of YAP/TAZ nuclear translocation mediated by Giα subunit of CXCR1/CXCR2. Red lines represent inhibitory effects of DF2755A.