title: Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A.
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.
authors: 1] Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan [2] National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors: H-C
authors: HC
authors: Yu
authors: 1] Division of Hematology and Oncology, Department of Medicine, Taipei Veterans' General Hospital, Taipei, Taiwan [2] Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.
authors: M-H
authors: MH
authors: Hung
authors: 1] Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan [2] School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Y-L
authors: YL
authors: Chen
authors: 1] Department of Pathology, St. Martin De Porres Hospital, Chiayi, Taiwan [2] School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors: P-Y
authors: PY
authors: Chu
authors: Medical Research Center, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan.
authors: C-Y
authors: CY
authors: Wang
authors: Medical Research Center, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan.
authors: T-T
authors: TT
authors: Chao
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: C-Y
authors: CY
authors: Liu
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: C-W
authors: CW
authors: Shiau
authors: 1] Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan [2] National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors: K-F
authors: KF
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D045744:Cell Line, Tumor; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2