Fenretinide-induced apoptosis of Huh-7 hepatocellular carcinoma is retinoic acid receptor β dependent

• DOI: 10.1186/1471-2407-7-236
• Publication Date: 2008-01-01T07:13:44Z
• Authors: Pengli Bu; Yu-Jui Yvonne Wan
• Keywords: Cancer Research; Fenretinide; Epidemiology; Receptors, Retinoic Acid; Retinoic Acid; Apoptosis; Generic/pharmacokinetics/ therapeutic use; Receptors; 2.1 Biological and endogenous factors; Aetiology; RC254-282; Cancer; 0303 health sciences; Tumor; Caspase 3; Communication; Liver Disease; Liver Neoplasms; Drugs; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 3. Good health; Gene Expression Regulation, Neoplastic; Oncology; Patient Satisfaction; Public Health and Health Services; Attitude to Health; Biotechnology; Research Article; Epilepsy/ drug therapy/psychology; Liver Cancer; Transcriptional Activation; Anticonvulsants/pharmacokinetics/ therapeutic use; Carcinoma, Hepatocellular; Oncology and Carcinogenesis; 610; Antineoplastic Agents; Phosphatidylserines; Cell Line; 03 medical and health sciences; Rare Diseases; Patient Education as Topic; Cell Line, Tumor; Genetics; In Situ Nick-End Labeling; Humans; Oncology & Carcinogenesis; Physician-Patient Relations; Neoplastic; Biomedical and Clinical Sciences; Carcinoma; Hepatocellular; Oncology and carcinogenesis; Therapeutic Equivalency; Gene Expression Regulation; Digestive Diseases

Retinoids are used to treat several types of cancer; however, their effects on liver cancer have not been fully characterized. To investigate the therapeutic potential of retinoids on hepatocellular carcinoma (HCC), the present study evaluates the apoptotic effect of a panel of natural and synthetic retinoids in three human HCC cell lines as well as explores the underlying mechanisms.Apoptosis was determined by caspase-3 cleavage using western blot, DNA double-strand breaks using TUNEL assay, and phosphatidylserine translocation using flow cytometry analysis. Gene expression of nuclear receptors was assessed by real-time PCR. Transactivation assay and chromatin immunoprecipitation (ChIP) were conducted to evaluate the activation of RXRalpha/RARbeta pathway by fenretinide. Knockdown of RARbeta mRNA expression was achieved by siRNA transfection.Our data revealed that fenretinide effectively induces apoptosis in Huh-7 and Hep3B cells. Gene expression analysis of nuclear receptors revealed that the basal and inducibility of retinoic acid receptor beta (RARbeta) expression positively correlate with the susceptibility of HCC cells to fenretinide treatment. Furthermore, fenretinide transactivates the RXRalpha/RARbeta-mediated pathway and directly increases the transcriptional activity of RARbeta. Knockdown of RARbeta mRNA expression significantly impairs fenretinide-induced apoptosis in Huh-7 cells.Our findings reveal that endogenous expression of retinoids receptor RARbeta gene determines the susceptibility of HCC cells to fenretinide-induced apoptosis. Our results also demonstrate fenretinide directly activates RARbeta and induces apoptosis in Huh-7 cells in a RARbeta-dependent manner. These findings suggest a novel role of RARbeta as a tumor suppressor by mediating the signals of certain chemotherapeutic agents.