IP3R3 silencing induced actin cytoskeletal reorganization through ARHGAP18/RhoA/mDia1/FAK pathway in breast cancer cell lines.

Cell morphology is altered in the migration process, and the underlying cytoskeleton remodeling is highly dependent of intracellular Ca2+ concentration. Many calcium channels are known to be involved in migration. Inositol 1,4,5-trisphosphate receptor (IP3R) was demonstrated to be implicated in breast cancer cells migration, but its involvement in morphological changes during the migration process remains unclear. In the present work, we showed that IP3R3 expression was correlated to cell morphology. IP3R3 silencing induced rounding shape and decreased adhesion in invasive breast cancer cell lines. Moreover, IP3R3 silencing decreased ARHGAP18 expression, RhoA activity, Cdc42 expression and Y861FAK phosphorylation. Interestingly, IP3R3 was able to regulate profilin remodeling, without inducing any myosin II reorganization. IP3R3 silencing revealed an oscillatory calcium signature, with a predominant oscillating profile occurring in early wound repair. To summarize, we demonstrated that IP3R3 is able to modulate intracellular Ca2+ availability and to coordinate the remodeling of profilin cytoskeleton organization through the ARHGAP18/RhoA/mDia1/FAK pathway.