Research Paper Volume 12, Issue 2 pp 1928—1951

Autocrine CXCL8-dependent invasiveness triggers modulation of actin cytoskeletal network and cell dynamics

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.