Tunicamycin induces resistance to camptothecin and etoposide in human hepatocellular carcinoma cells: Role of cell-cycle arrest and GRP78
Journal
Naunyn-Schmiedeberg's Archives of Pharmacology
Journal Volume
380
Journal Issue
5
Pages
373-382
Date Issued
2009
Author(s)
Abstract
Hepatocellular carcinoma is chemoresistant to many anticancer drugs. Tunicamycin, an N-glycosylation inhibitor, causes unfolded protein response and is widely used as pharmacological inducer of endoplasmic reticulum stress. In this study, several designs were used to investigate the resistance mechanism to camptothecin and etoposide in hepatocellular carcinoma Hep3B cells. Tunicamycin significantly inhibited apoptosis induced by camptothecin or etoposide. Tunicamycin neither modified the topoisomerase levels nor inhibited the ATM activation caused by camptothecin and etoposide. The data suggest that tunicamycin-induced resistance may result from the downstream events of drug-trapped topoisomerase-DNA complexes and DNA double-strand breaks. Camptothecin and etoposide caused an increase of protein expression of several cell-cycle regulators and induced the cleavage of Bcl-2 family of proteins. These intracellular molecular events were abolished by tunicamycin. A design of postaddition of tunicamycin demonstrated that G1 checkpoint arrest contributed to the resistance mechanism. Curcumin, another G1 arrest-inducing agent in this study, was able to induce a similar resistant effect. Furthermore, the cells transfected with GRP78 siRNA were partly resistant to tunicamycin-induced apoptosis but not the inhibitory effect on cell-cycle regulators indicating that GRP78 and G1 arrest are two independent factors to tunicamycin-induced resistance mechanism. In conclusion, the data suggest that tunicamycin induces the resistance to topoisomerase inhibitors through GRP78 up-regulation and G1 arrest of the cell cycle. The findings also prompt the deliberation that the resistance can be caused during combined administration of chemotherapeutic drugs and Chinese herbal medicines, which induce endoplasmic reticulum stress and/or cell-cycle arrest in cancer cells. ? 2009 Springer-Verlag.
Subjects
Cell-cycle arrest; Drug resistance; GRP78; Human hepatocellular carcinoma; Tunicamycin
SDGs
Other Subjects
ATM protein; camptothecin; curcumin; DNA topoisomerase; etoposide; glucose regulated protein 78; small interfering RNA; tunicamycin; apoptosis; article; cell cycle arrest; cell cycle G1 phase; drug inhibition; drug mechanism; drug resistance; human; human cell; liver cell carcinoma; protein expression; Antineoplastic Agents, Phytogenic; Apoptosis; Camptothecin; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Drug Resistance, Neoplasm; Etoposide; G1 Phase; Heat-Shock Proteins; Humans; Liver Neoplasms; Tunicamycin
Type
journal article