Enhanced antitumor effect of shikonin by inhibiting Endoplasmic Reticulum Stress via JNK/c-Jun pathway in human glioblastoma stem cells.

Though previous study demonstrated that shikonin could exert its antitumor activity by inducing apoptosis and necrosis, the pro-survival mechanisms involved in its antitumor process are still little to know. In the present study, for the first time, we found a protective mechanism was simultaneously activated which caused the reduced sensitivity of glioblastoma stem cells (GSCs) to the cytotoxicity of shikonin. Reduced active caspase-9 expression and enhanced mitochondrial membrane potential (MMP) were intriguingly observed within 24 h treatment by shikonin in GSCs. Further investigation identified that Endoplasmic Reticulum Stress (ERS) was involved in its antitumor process, which compromised the cytotoxicity of shikonin toward GSCs. Inhibiting ERS by 4-phenylbutyric acid (4-PBA) markedly enhanced the cytotoxicity of shikonin in GSCs. The consistent result was simultaneously observed in the GSCs-xenografted mice. Furthermore, our results identified that JNK/c-Jun pathway was involved in the antitumor process of shikonin, providing a mechanism by which ERS reduced the cytotoxicity of shikonin toward GSCs. Altogether, the novel observation in the present study identified that inhibiting ERS would be an attractive new approach to enhance the therapeutic potency of shikonin toward GSCs.