TIS21/BTG2 inhibits doxorubicin-induced stress fiber-vimentin networks via Nox4-ROS-ABI2-DRF-linked signal cascade.

Activities of TIS21/BTG2 gene regulating cancer cell senescence were investigated in hepatoma cells by using low dose doxorubicin (Doxo, 100ng/mL). Treatment of Huh7 cells with Doxo increased linear actin nucleation e.g., transverse arcs and ventral stress fibers, as opposed to loss of filopodia. The linear actin nucleation was accompanied with thick vimentin networks at periphery of the cells, when examined by super-resolution STED microscope. However, expression of TIS21 inhibited ABI2-DRF pathway by inhibiting DRF expression and reducing ABI2 protein stability. The change lead to downregulation of stress fiber formations and thick vimentin networks at the periphery of Huh7 cells. In addition, TIS21 inhibited NADPH oxidase 4 (Nox4)-derived reactive oxygen species (ROS) generation that regulates actin nucleator, DRF family gene expression. Taken together, TIS21 attenuated Doxo-induced cancer cell senescence by inhibiting linear actin nucleation via Nox4-ROS-ABI2-DRF signal cascade, implying that expression of TIS21 overcomes resistance of senescent cells to cancer chemotherapy via inhibiting linear actin nucleation.