Author: Wan Lun Wang ; Chun Yu Liu ; Tzu Ting Huang ; Ming Shen Dai ; Chun Teng Huang ; Yi Ting Chen ; Ka Yi Lau ; Ji Lin Chen ; Pei Yi Chu ; Ling Ming Tseng ; Chung Wai Shiau

BACKGROUNDTriple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC.METHODSData from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model.FINDINGSTCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter.INTERPRETATIONThese findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.

01 Jan 2018·Journal of Pharmacology and Experimental Therapeutics

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

Article

Author: Lai, Chih-Cheng ; Chen, Kuen-Feng ; Lin, Hen-I. ; Shiau, Chung-Wai ; Huang, Yuh-Chin T. ; Yu, Chong-Jen ; Chen, Yen-Lin ; Chen, Pao-Tzu ; Chao, Ting-Ting ; Wang, Cheng-Yi ; Tsai, Yi-Ting

01 Nov 2014·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Yu, Chong-Jen ; Lin, Hen-I ; Huang, Yuh-Chin T ; Chao, Ting-Ting ; Chen, Pao-Tzu ; Tsai, Yi-Ting ; Lai, Chih-Cheng ; Chen, Kuen-Feng ; Chen, Yen-Lin ; Wang, Cheng-Yi ; Shiau, Chung-Wai

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	TW	Taipei Veterans General Hospital	-
Breast Cancer	Preclinical	TW	National Taiwan University	-
Breast Cancer	Preclinical	TW	National Taiwan University Hospital	-
Breast Cancer	Preclinical	TW	National Yang Ming University	-
Non-Small Cell Lung Cancer	Preclinical	TW	National Taiwan University	-
Non-Small Cell Lung Cancer	Preclinical	TW	National Taiwan University Hospital	-
Non-Small Cell Lung Cancer	Preclinical	TW	National Yang Ming University	-

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