Retinoid upregulates the sensitivity of cancer cells to a cytokine by inducing the cytokine receptor

点击翻译按钮获取中文摘要

Acyclic retinoid, a synthetic retinoid analog, as well as interferons (IFNs)-α and -β induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7,HuH7,PLC/PRF/5,HLE and HLF). This synergism was only observed when cells were pretreated with the aeyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with anti-type 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2',5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably due to lack of IFNR and STAT1 up-regulation. These results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-β.