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

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.

2018-01-01·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

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

2014-11-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

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

3区 · 医学

Article

作者: Lin, Hen-I ; Yu, Chong-Jen ; Huang, Yuh-Chin T ; Chen, Pao-Tzu ; Chao, Ting-Ting ; 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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适应症	最高研发状态	国家/地区	公司	日期
三阴性乳腺癌	临床前	中国台湾	Taipei Veterans General Hospital	2016-07-15
乳腺癌	临床前	中国台湾	国立阳明大学	-
乳腺癌	临床前	中国台湾	国立台湾大学	-
乳腺癌	临床前	中国台湾	National Taiwan University Hospital	-
非小细胞肺癌	临床前	中国台湾	国立台湾大学	-
非小细胞肺癌	临床前	中国台湾	国立阳明大学	-
非小细胞肺癌	临床前	中国台湾	National Taiwan University Hospital	-