Bortezomib sensitizes HCC cells to CS-1008, an antihuman death receptor 5 antibody, through the inhibition of CIP2A

Chen K.-F.Yu H.-C.Liu C.-Y.Chen H.-J.Chen Y.-C.Hou D.-R.PEI-JER CHENANN-LII CHENG2021-07-032021-07-0320111535-7163https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984548924&doi=10.1158%2f1535-7163.MCT-10-0794&partnerID=40&md5=de25bb4514b602f311f987da33563bf2https://scholars.lib.ntu.edu.tw/handle/123456789/568534Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. ?2011 AACR.[SDGs]SDG3bortezomib; cancerous inhibitor of protein phosphatase 2a; phosphoprotein phosphatase 2A; protein kinase B; small interfering RNA; tigatuzumab; unclassified drug; animal experiment; animal model; apoptosis; article; cancer cell culture; cancer combination chemotherapy; controlled study; down regulation; drug mechanism; drug potentiation; drug sensitivity; human; human cell; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expressionBortezomib sensitizes HCC cells to CS-1008, an antihuman death receptor 5 antibody, through the inhibition of CIP2Ajournal article10.1158/1535-7163.MCT-10-07942-s2.0-84984548924