Doxorubicin induces ZAK[alpha] overexpression with a subsequent enhancement of apoptosis and attenuation of survivability in human osteosarcoma cells

Human osteosarcoma (OS) is a malignant cancer of the bone. It exhibits a characteristic malignant osteoblastic transformation and produces a diseased osteoid. A previous study demonstrated that doxorubicin (DOX) chemotherapy decreases human OS cell proliferation and might enhance the relative RNA expression of ZAK. However, the impact of ZAK[alpha] overexpression on the OS cell proliferation that is inhibited by DOX and the molecular mechanism underlying this effect are not yet known. ZAK is a protein kinase of the MAPKKK family and functions to promote apoptosis. In our study, we found that ZAK[alpha] overexpression induced an apoptotic effect in human OS cells. Treatment of human OS cells with DOX enhanced ZAK[alpha] expression and decreased cancer cell viability while increasing apoptosis of human OS cells. In the meantime, suppression of ZAK[alpha] expression using shRNA and inhibitor D1771 both suppressed the DOX therapeutic effect. These findings reveal a novel molecular mechanism underlying the DOX effect on human OS cells. Taken together, our findings demonstrate that ZAK[alpha] enhances the apoptotic effect and decreases cell viability in DOX-treated human OS cells.