Curcumin Boosts Natural Killer Cell-Based Immunotherapy in Impeding Progression of Hepatocellular Carcinoma Through Androgen Receptor/UL16 Binding Protein-2 Signal

Abstract

Hepatocellular carcinoma (HCC) is hardly curable with present treatment modalities, especially for those in advanced disease stage. Several chronic hepatic disorders, including alcoholic liver disease, cirrhotic and viral hepatitis, can ultimately lead to occurrence of HCC. This study investigated the effects of curcumin on natural killer (NK) cell-based immunotherapies being applied to restrain the progress of HCC, and disclose valid message for better clinical application of curcumin. After receiving curcumin treatment, the HCC cells were co-cultured with NK cells to study cytotoxicity of NK cells. After thein vitrocytotoxicity assay, we determined the function of curcumin in modulating the cytotoxicity of NK cells. Additionally, the mechanism of curcumin on HCC cells was investigated by utilizing the following techniques: lentiviral infection/transfection, qPCR and Western-blot, thereby exploring the genetic alterations of differently treated HCC cells. HCC cell lines (SK-Hep1 and SUN423) were studied, and findings confirmed that curcumin significantly strengthened the cytotoxic NK cells to kill HCC cells. This effect was mainly achieved through regulating androgen receptor (AR)/UL162 signal, which led to efficacy enhancement of NK cell-based immunotherapy. Moreover, secretion of interferon-γwhich is an immunoregulator executing an anti-tumor effect was also elevated. In addition, curcumin strengthened the expression of ULBP2 in SK-Hep1 and SUN423 cells, while relatively weakening the expression of androgen receptor. The findings from this study can provide a theoretical base for further research and development of curcumin as a beneficial suppressor of HCC progression. We found that the cytotoxicity of NK cells towards HCC cells was gradually elevated as the HCC cells were treated with increased concentration of curcumin. Meanwhile, the secretion of interferon-γ, which was an immunoregulator exerting an anti-tumor effect, was also gradually elevated. In addition, the expression levels of ULBP2 in SK-Hep1 and SUN423 cells were continuously enhanced with increased concentration of curcumin in the pre-treatment of HCC cells, while the expression of androgen receptor was relatively weakened. Similar results were also obtained after the overexpression or knockdown of androgen receptor (AR) gene in SK-Hep1 and SUN423 cells. Therefore, this study found that curcumin can boost the NK cell-based immunotherapy in impeding progression of HCC through the androgen receptor/ULBP2 signal.