The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells

Liu, Chun Yu; Huang, Tzu Ting; Chu, Pei Yi; Huang, Chun Yao; Lee, Chia-Han; Wang, Wan-Lun; Lau, Ka Yi; Tsai, Wen Chun; Chao, Tzu I.; Su, Jun-Ming; Chen, Ming-Huang; Shiau, Chung Wai; Tseng, Ling Ming; Chen, Kuen Feng

doi:10.1038/emm.2017.114

Cited by 31 publications

(22 citation statements)

References 49 publications

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“…1b, left and middle). It has been reported that Elk-1 upregulated CIP2A expression by interacting with the proximal CIP2A promoter [38], we found the expression level of CIP2A slightly positive correlated with Elk-1 level (Fig. 1b, right).…”

Section: Resultssupporting

confidence: 53%

Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression

et al. 2019

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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.

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Section: Resultssupporting

confidence: 53%

Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression

et al. 2019

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“…Among them, nintedanib and SC-78 significantly increase SHP-1 activity without affecting its expression [99, 100], while 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) and SC-2001 largely induce the expression of SHP-1 [101, 102]. All these SHP-1 activators were also shown to inhibit STAT3 phosphorylation and the expression of its downstream target genes, thus suppressing TNBC cell growth and migration and inducing apoptosis in vitro and in vivo [99–102]. In addition, isolinderalactone was reported to increase SOCS3 expression and then enhance SOCS3-mediated STAT3 dephosphorylation and inactivation [103].…”

Section: Targeting Stat3 For Tnbc Prevention and Therapymentioning

confidence: 99%

STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

Qin

Li²,

Zhang³

et al. 2019

J Exp Clin Cancer Res

259

187

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Triple negative breast cancer (TNBC), which is typically lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents the most aggressive and mortal subtype of breast cancer. Currently, only a few treatment options are available for TNBC due to the absence of molecular targets, which underscores the need for developing novel therapeutic and preventive approaches for this disease. Recent evidence from clinical trials and preclinical studies has demonstrated a pivotal role of signal transducer and activator of transcription 3 (STAT3) in the initiation, progression, metastasis, and immune evasion of TNBC. STAT3 is overexpressed and constitutively activated in TNBC cells and contributes to cell survival, proliferation, cell cycle progression, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immunosuppression, and stem cells self-renewal and differentiation by regulating the expression of its downstream target genes. STAT3 small molecule inhibitors have been developed and shown excellent anticancer activities in in vitro and in vivo models of TNBC. This review discusses the recent advances in the understanding of STAT3, with a focus on STAT3's oncogenic role in TNBC. The current targeting strategies and representative small molecule inhibitors of STAT3 are highlighted. We also propose potential strategies that can be further examined for developing more specific and effective inhibitors for TNBC prevention and therapy.

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“…Src homology region 2 domain-containing phosphatase 1 (ShP-1) is a non-receptor protein tyrosine phosphatase and serves as a tumor suppressor gene in numerous cancer types. Liu et al(75) demonstrated that ShP-1 expression levels are downregulated in the majority of tumor types and correlate with high expression levels of p-STAT3 expression. Thus, the ShP-1/p-STAT3 signaling axis may represent a potential therapeutic target and a clinical prognostic indicator in patients with cancer.…”

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Overview of the STAT‑3 signaling pathway in cancer and the development of specific inhibitors (Review)

Mohammad

Liu

2020

Oncol Lett

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Signal transducer and activator of transcription (STAT) proteins represent novel therapeutic targets for the treatment of cancer. In particular, STAT-3 serves critical roles in several cellular processes, including the cell cycle, cell proliferation, cellular apoptosis and tumorigenesis. Persistent activation of STAT-3 has been reported in a variety of cancer types, and a poor prognosis of cancer may be associated with the phosphorylation level of STAT-3. Furthermore, elevated STAT-3 activity has been demonstrated in a variety of mammalian cancers, both in vitro and in vivo. This indicates that STAT-3 serves an important role in the progression of numerous cancer types. A significant obstacle in developing STAT-3 inhibitors is the demonstration of the antitumor efficacy in in vivo systems and the lack of animal models for human tumors. Therefore, it is crucial to determine whether available STAT-3 inhibitors are suitable for clinical trials. Moreover, further preclinical studies are necessary to focus on the impact of STAT-3 inhibitors on tumor cells. When considering STAT-3 hyper-activation in human cancer, selective targeting to these proteins holds promise for significant advancement in cancer treatment. In the present study, advances in our knowledge of the structure of STAT-3 protein and its regulatory mechanisms are summarized. Moreover, the STAT-3 signaling pathway and its critical role in malignancy are discussed, in addition to the development of STAT-3 inhibitors in various cancer types. Contents 1. Introduction 2. STAT-3 structure 3. STAT-3 signal transduction cascade 4. Target genes regulated by STAT-3 5. Advances in antitumor therapeutics targeting STAT-3 6. Conclusions

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The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells

Cited by 31 publications

References 49 publications

Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression

Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression

STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

Overview of the STAT‑3 signaling pathway in cancer and the development of specific inhibitors (Review)

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