Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma

Yu, Hui; Chen, Hui Ju; Chang, Ya Ling; Liu, Chun Yu; Shiau, Chung Wai; Cheng, Ann‐Lii; Chen, Kuen Feng

doi:10.1016/j.bcp.2012.11.009

Cited by 44 publications

(32 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While there is expanding interest in targeting CIP2A for cancer therapy due to its high expression in multiple cancers [18,20,[35][36][37][38][39][40], multiple oncogenic effects [17,[41][42][43][44], and roles in chemoresistance [45][46][47][48], the exact method of CIP2A inhibition has been elusive. CIP2A has no known enzymatic function; rather, it has been suggested to multimerize and act as a scaffolding protein [28].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

Using yeast two-hybrid analysis, we identified several novel protein interactions for the oncoprotein Cancerous Inhibitor of PP2A (CIP2A) and confirmed a subset of these interactions in human cancer cell lines. Analysis of the interaction in prostate carcinoma cells between CIP2A and leucine-rich repeat-containing protein 59 (LRRC59) suggests that CIP2A is translocated into the nucleus at G2/M through its association with LRRC59. Recent work by others has demonstrated that nuclear CIP2A disrupts mitotic checkpoints, which promotes deregulation of the cell cycle and increases cancerous phenotypes. Thus, we provide a novel therapeutic mechanism for inhibiting CIP2A function in cancerous cells via targeting the CIP2A-LRRC59 interaction.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…16 CIP2A is a cellular inhibitor of the important tumor-suppressor protein, protein phosphatase 2A (PP2A). 17 PP2A functions as a serine/threonine protein phosphatase that regulates several important oncogenic proteins such as c-Myc, ERK and Akt.…”

mentioning

confidence: 99%

Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A

Hung

Chen

et al. 2014

Cell Death Dis

View full text Add to dashboard Cite

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.

show abstract

“…PP2A activity was measured in fresh cells as described previously (Yu et al, 2013a) using PP2A DuoSet IC activity assay kit (R&D Systems, Minneapolis, MN), according to the manufacturer's description. Briefly, an immobilized capture antibody specific for the catalytic subunit of PP2A that binds both active and inactive PP2A was used.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous study, we found that erlotinib could also suppress CIP2A and that it induced apoptosis in vivo and in vitro in hepatocellular carcinoma (Yu et al, 2013a) and lung cancer (Wang et al, 2014). Erlotinib is a quinazoline derivative with amino substitutes at position 4 (Hennequin et al, 1996;van Muijlwijk-Koezen et al, 2000;Shreder et al, 2004;Morphy, 2010).…”

Section: Introductionmentioning

confidence: 99%

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Chao¹,

Wang²,

Lai

et al. 2014

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.

show abstract

Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma

Cited by 44 publications

References 47 publications

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

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

Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Contact Info

Product

Resources

About