Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A
Journal
Cell Death and Disease
Journal Volume
5
Journal Issue
7
Date Issued
2014
Author(s)
Kuen-Feng Chen
Abstract
Protein phosphatase 2A (PP2A) is a tumor suppressor, which is functionally defective in various cancers. Previously, we found that PP2A activity determined the anticancer effect of bortezomib and erlotinib in hepatocellular carcinoma (HCC) cells. Here, we tested a novel erlotinib derivative, TD52, in four HCC cell lines, PLC5, Huh-7, Hep3B and Sk-Hep1. Using MTT and flow cytometry, we showed that TD52 had more potent apoptotic effects than erlotinib in HCC cells. TD52-induced apoptosis was associated with dose- and time- dependent reactivation of PP2A and downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A) and p-Akt. Inhibition of PP2A or ectopic expression of CIP2A or Akt in PLC5 cells abolished the effects of TD52. Furthermore, we demonstrated that TD52 affected the binding of Elk-1 to the proximal promoter of the CIP2A gene, thus downregulating transcription of CIP2A. Importantly, TD52-induced tumor inhibition was associated with reactivation of PP2A and downregulation of CIP2A and p-Akt in vivo. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A determines the apoptotic effect induced by TD52. Our findings disclose the therapeutic mechanism of this novel targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy. ? 2014 Macmillan Publishers Limited.
SDGs
Other Subjects
cancerous inhibitor of protein phosphatase 2a; erlotinib; phosphoprotein phosphatase 2A; protein; protein kinase B; sorafenib; td 52; transcription factor Elk 1; unclassified drug; antineoplastic agent; autoantigen; erlotinib; KIAA1524 protein, human; membrane protein; phosphoprotein phosphatase 2; protein kinase B; quinazoline derivative; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer cell line; cancer inhibition; cancer size; cell viability; comparative effectiveness; concentration response; controlled study; cross linking; dose response; down regulation; drug potency; drug targeting; enzyme activity; enzyme inhibition; enzyme reactivation; flow cytometry; human; human cell; in vivo study; liver cell carcinoma; major clinical study; male; mouse; MTT assay; nonhuman; priority journal; promoter region; protein binding; protein degradation; protein dephosphorylation; protein expression; protein targeting; treatment duration; animal; chemistry; drug effects; drug screening; enzymology; gene expression regulation; genetics; liver cell carcinoma; liver tumor; metabolism; nude mouse; pathophysiology; tumor cell line; Animals; Antineoplastic Agents; Apoptosis; Autoantigens; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Membrane Proteins; Mice; Mice, Nude; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Quinazolines; Xenograft Model Antitumor Assays
Type
journal article