Upregulation of retinoic acid receptor-β reverses drug resistance in cholangiocarcinoma cells by enhancing susceptibility to apoptosis.
Retinoic acid receptor β (RARβ), a known tumor suppressor gene, is frequently silenced in numerous malignant types of tumor. Recent reports have demonstrated that loss of RARβ expression may be responsible, in part, for the drug resistance observed in clinical trials. However, little is known about the role of RARβ in regulating drug sensitivity in patients with cholangiocarcinoma (CCA) with a high risk of mortality and poor outcomes. In the present study, low RARβ expression was observed in the majority of CCA tissues investigated (28/33, 84.8%). In addition, the CCA cell line QBC939, which exhibits low RARβ expression, was found to be significantly resistant to chemotherapeutic agents compared with SK‑ChA‑1, MZ‑ChA‑1 and Hccc9810 CCA cell lines, which exhibit high RARβ expression. Furthermore, upregulation of RARβ significantly enhanced the sensitivity of QBC939 cells to common chemotherapeutic agents both in vitro and in vivo. Upregulation of RARβ was shown to increase the expression of proapoptotic genes bax, bak and bim, in addition to caspase‑3 activity, and decrease the expression of antiapoptotic genes bcl‑2, bcl‑xL and mcl‑1. As a result, CCA cells were more susceptible to caspase‑dependent apoptosis. Taken together, these data suggest that RARβ upregulation rendered CCA cells more sensitive to chemotherapeutic agents by increasing the susceptibility of cells to caspase-dependent apoptosis. These results support the hypothesis that RARβ may be an ideal chemosensitization target for the treatment of patients with drug-resistant CCA.
Biobank, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Hong-Yue
HY
Ren
Department of Surgical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen Cancer Center, Xiamen, Fujian 361003, P.R. China.
Bo
B
Chen
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, P.R. China.
Gui-Li
GL
Huang
Biobank, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Yu
Y
Liu
Biobank, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Dong-Yan
DY
Shen
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D005472:Fluorouracil