Berbamine inhibits the growth of liver cancer cells and cancer initiating cells by targeting Ca2+/Calmodulin-dependent protein kinase II

摘要

Liver cancer is the third leading cause of cancer deaths worldwide but no effective treatment toward liver cancer is available so far. Therefore, there is an unmet medical need to identify novel therapies to efficiently treat liver cancer and improve the prognosis of this disease. Here we report that berbamine (BBM) and one of its derivatives, bbd24, potently suppressed liver cancer cell proliferation and induced cancer cell death by targeting Ca²⁺/calmodulin-dependent protein kinase II (CAMKII). Furthermore, BBM inhibited the in vivo tumorigenicity of liver cancer cells in NOD/SCID mice, and down-regulated the self-renewal abilities of liver cancer initiating cells. Chemical inhibition or short hairpin RNAs-mediated knockdown of CAMKII recapitulated the effects of BBM, while overexpression of CAMKII promoted cancer cell proliferation and increased the resistance of liver cancer cells to BBM treatments. Western blot analyses of human liver cancer specimens showed that CAMKII was hyperphosphorylated in liver tumors compared with the paired peri-tumor tissues, which supports a role of CAMKII in promoting human liver cancer progression and the potential clinical use of BBM for liver cancer therapies. Our data suggests that BBM and its derivatives are promising agents to suppress liver cancer growth by targeting CAMKII.