Tunicamycin Enhances TRAIL-induced Apoptosis In Human Colon Cancer Cells

All over the world,about 5 million people died of cancer.Colorectal cancer(CRC)is one of the human malignant tumors.Westerners behave higher incidence of colon cancer,while in the past 30 years,the majority of countries and regions including China colon cancer incidence of a disease is on the rise.Looking for specific inhibition of colon cancer cell proliferation and promote apoptosis of drugs or drug combinations and reveal its action mechanism is one of the hot spot of research.Tumor necrosis factor related apoptosis inducing ligand TRAIL which can specific killing tumor cells and virtually non-toxic side effects on the normal cells,is the hope of antitumor drugs.But a wide variety of tumor cells showed resistance to TRAIL,the TRAIL application in tumor treatment is limited.We found tunicamycin in restoring TRAIL sensitivity function in human colon cancer HCT116 cells and HT29 cells and its mechanism of action.On a cellular mechanistic level,tunicamycin induced the TRAIL death receptors on the cell membrane surface DR5 expression level and DR4 deglycosylation.Knockdown of DR5 expression by specific siRNAs significantly inhibited tunicamycin TRAIL mediated cell viability.But knockdown of DR4 expression have no function.The up-regulation of DR5 was regulated by C/EBP homologous transcription factor protein CHOP as CHOP siRNA considerably abolished the DR5 induction.The up-regulation of CHOP was regulated by JNK signaling pathway as JNK inhibitor SP600125 considerably abolished the CHOP induction.In addition,tunicamycin inhibited EGFR glycosylation and the downstream signaling pathways,Akt and ERK signaling pathway activation,which might also contribute to TRAIL sensitization by tunicamycin in colon cancer cells.In summary,tunicamycin observably enhanced TRAIL-induced apoptosis through DR5 upregulation which mediated by JNK-CHOP pathway and the inhibition of the EGFR glycosylation and the downstream signaling pathways.