GRP78 mediates the therapeutic efficacy of curcumin on colon cancer
Glucose-regulated protein 78 (GRP78) is the key regulator of endoplasmic reticular (ER) function. Expression of GRP78 was correlated with malignancy in different cancers. However, the role of GRP78 in the cytotoxic effect of curcumin on colon cancer cells is still unclear. A silencing RNA (siRNA) technique was used to knock down GRP78 expression. The anticancer effects of curcumin were assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometric cell cycle analysis, and a terminal dexynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. HT-29 cells expressed lower GRP78 compared with DLD-1 cells. The MTT assay revealed that HT-29 cells were more resistant to curcumin treatment than DLD-1 cells. GRP78KD cells showed more resistance to curcumin treatment compared with scrambled control cells. Overexpressed GRP78 in HT-29 cells increased the sensitivity to curcumin treatment. According to the cell cycle analysis and TUNEL assay, we found that apoptosis dramatically increased in scrambled control cells compared to GRP78KD DLD-1 cells after curcumin treatment. Finally, we evaluated levels of Bcl-2, BAX, and Bad and found that an increase of Bcl-2 level was observed in GRP78KD cells treated with curcumin. Those results were consistent with the increasing of resistance to curcumin after silencing of GRP78. The levels of GRP78 expression might determine the therapeutic efficacy of curcumin against colon cancer cells.
KeywordsColon cancer Antiproliferation Curcumin GRP78
Glucose-regulated protein 78
This study was supported by grants from National Science Council (NSC101-2314-B-038-029-MY3 and NSC101-2314-B-038-016-MY3).
Conflicts of interest
- 8.Hasima N, Aggarwal BB. Cancer-linked targets modulated by curcumin. Int J Biochem Molec Biol. 2012;3:328–51.Google Scholar
- 20.Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA. Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res. 2006;66:1702–11.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Chen B, Zhang Y, Wang Y, Rao J, Jiang X, Xu Z: Curcumin inhibits proliferation of breast cancer cells through nrf2-mediated down-regulation of fen1 expression. The Journal of Steroid Biochemistry and Molecular Biology 2014.Google Scholar
- 32.Xie YQ, Wu XB, Tang SQ. Curcumin treatment alters erk-1/2 signaling in vitro and inhibits nasopharyngeal carcinoma proliferation in mouse xenografts. Int J Clinic Experiment Med. 2014;7:108–14.Google Scholar
- 41.Shehzad A, Lee J, Huh TL, Lee YS: Curcumin induces apoptosis in human colorectal carcinoma (hct-15) cells by regulating expression of prp4 and p53. Molecules and cells 2013.Google Scholar
- 42.Kim HJ, Park SY, Park OJ, Kim YM. Curcumin suppresses migration and proliferation of Hep3B hepatocarcinoma cells through inhibition of the Wnt signaling pathway. Molec Med Rep. 2013;8:282–6.Google Scholar
- 43.Teiten MH, Dicato M, Diederich M: Curcumin as a regulator of epigenetic events. Molecular nutrition & food research 2013.Google Scholar