the enzyme capain-6 is negatively controlled by the proteoglycan syndecan-2, that controls the activity of various cytokines and growth factors and also modulates apoptosis and response to cytotoxic agents in osteosarcoma cell lines. Syndecan-2 exerts its pro-apoptotic function through modulation of the endothelin-1/NFkappaB signaling and through downregulation of calpain-6. Calpain-6 expression in osteosarcoma cells depends on endothelin-1, a mediator of the tumor progression in bone. Syndecan-2 overexpression alters ERK1/2, PI3K/AKT and NFjB pathways that are calpain-6-promoting signals downstream of endothelin-1
inhibition of calpain-6 with shRNA results in decreased proliferation, increased spontaneous apoptosis and increased sensitivity to doxorubicin and also methotrexate in responsive and resistant osteosarcoma cells
knockdown of calpain-6 in NIH-3T3 cells results in Rac1 activation, which promotes cell migration, spreading and lamellipodial protrusion. Upon knockdown of calpain-6, GEF-H1 translocates from microtubules to the lamellipodial region and to interact with Rac1. RhoA activity is decreased upon knockdown of calpain-6
calpain-6 is a microtubule-stabilizing protein that regulates Rac1 activity and cell motility through interaction with the Rho guanine-nucleotide-exchange factor GEF-H1. Calpain-6 is involved in the regulation of the organization of cortical actin and subsequent changes in cell motility and morphology, independent of the proteolytic activity of calpains
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calpain-6 expression depends on NFkappaB activity and endothelin-1. Calpain-6 expression is increased by doxorubicin; calpain-6 expression in osteosarcoma cells depends on endothelin-1. Calpain-6 is increased by doxorubicin (10 ng/ml) and expressed at higher levels in doxorubicin-resistant U2OS osteosarcoma-derived cells as compared to responsive cells