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

Abstract Cell morphology is altered in the migration process, and the underlying cytoskeleton remodeling is highly dependent of intracellular Ca 2+ concentration. Many calcium channels are known to be involved in migration. Inositol 1,4,5-trisphosphate receptor (IP 3 R) 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 IP 3 R3 expression was correlated to cell morphology. IP 3 R3 silencing induced rounding shape and decreased adhesion in invasive breast cancer cell lines. Moreover, IP 3 R3 silencing decreased ARHGAP18 expression, RhoA activity, Cdc42 expression and Y861 FAK phosphorylation. Interestingly, IP 3 R3 was able to regulate profilin remodeling, without inducing any myosin II reorganization. IP 3 R3 silencing revealed an oscillatory calcium signature, with a predominant oscillating profile occurring in early wound repair. To summarize, we demonstrated that IP 3 R3 is able to modulate intracellular Ca 2+ availability and to coordinate the remodeling of profilin cytoskeleton organization through the ARHGAP18/RhoA/mDia1/FAK pathway.