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.

Down-regulation of RASA1 Is Associated with Poor Prognosis in Human Hepatocellular Carcinoma

“…The slides were photographed with the microscope (BX50, OLYMPUS, Japan, Tokyo). In liver cancer specimens, the detailed scores for IHC were defined as described previously (16,17), and the IHC score of RASA1 for each specimen were defined as the cell staining intensity (0=nil; 1=weak; 2=moderate; and 3=strong) multiplied by the percentage of labeled cells (0-100%), leading to scores from 0 to 300. A score higher than the mean was defined as 'high' expression, while a score equal to or lower than the mean was categorized as 'low' expression in tumor.…”

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

“…PP2A is a serine/threonine phosphatase that has a critical role in regulating various cellular processes, including signaling transduction, protein synthesis, cell cycle determination, metabolism, apoptosis and stress response (26). Because loss of PP2A function has been identified in various malignant diseases such as cancer of the lung, liver, colon, and breast, it has been reported that enhancing PP2A activity could be an effective approach for cancer treatment (27). Thus, we showed that by Atn-induced inhibition of CIP2A, activity of PP2A was significantly enhanced and expression of pAkt was downregulated in TNBCs cells.…”

Leucine-rich repeat-containing protein 59 mediates nuclear import of cancerous inhibitor of PP2A in prostate cancer cells

“…Cancerous inhibitor of PP2A (CIP2A) was first identified to inhibit PP2A and promote cell proliferation through stabilization of c-Myc [17]. CIP2A is over-expressed in a variety of cancers, including prostate cancer [18], and high expression correlates with poor prognosis [19][20][21] and contributes to drug resistance [22,23]. Recently, Huang et al demonstrated that depletion of CIP2A in castration-resistant cancers can sensitize prostate carcinoma cells to therapeutic agents [24].…”