Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

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Abstract

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories.

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Most cited references 114

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Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.

Kodappully Siveen, Sakshi Sikka, Rohit Surana … (2014)

Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade. Copyright © 2013 Elsevier B.V. All rights reserved.

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Protein-tyrosine phosphatases and cancer.

Arne Östman, F-D Böhmer, Carina Hellberg (2006)

Tyrosine phosphorylation is an important signalling mechanism in eukaryotic cells. In cancer, oncogenic activation of tyrosine kinases is a common feature, and novel anticancer drugs have been introduced that target these enzymes. Tyrosine phosphorylation is also controlled by protein-tyrosine phosphatases (PTPs). Recent evidence has shown that PTPs can function as tumour suppressors. In addition, some PTPs, including SHP2, positively regulate the signalling of growth-factor receptors, and can be oncogenic. An improved understanding of how these enzymes function and how they are regulated might aid the development of new anticancer agents.

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Strategies and Approaches of Targeting STAT3 for Cancer Treatment.

Steffanie L Furtek, Donald Backos, Christopher Matheson … (2016)

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates the expression of genes related to cell cycle, cell survival, and immune response associated with cancer progression and malignancy in a number of cancer types. Once activated, STAT3 forms a homodimer and translocates to the nucleus where it binds DNA promoting the translation of target genes associated with antiapoptosis, angiogenesis, and invasion/migration. In normal cells, levels of activated STAT3 remain transient; however, STAT3 remains constitutively active in approximately 70% of human solid tumors. The pivotal role of STAT3 in tumor progression has promoted a campaign in drug discovery to identify small molecules that disrupt the function of STAT3. A range of approaches have been used to identify novel small molecule inhibitors of STAT3, including high-throughput screening of chemical libraries, computational-based virtual screening, and fragment-based design strategies. The most common approaches in targeting STAT3 activity are either via the inhibition of tyrosine kinases capable of phosphorylating and thereby activating STAT3 or by preventing the formation of functional STAT3 dimers through disruption of the SH2 domains. However, the targeting of the STAT3 DNA-binding domain and disruption of binding of STAT3 to its DNA promoter have not been thoroughly examined, mainly due to the lack of adequate assay systems. This review summarizes the development of STAT3 inhibitors organized by the approach used to inhibit STAT3, the current inhibitors of each class, and the assay systems used to evaluate STAT3 inhibition and offers an insight into future approaches for small molecule STAT3 inhibitor development.

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Author and article information

Contributors

Terrence Piva: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 08 June 2017

Publication date Collection: June 2017

Volume: 18

Issue: 6

Electronic Location Identifier: 1234

Affiliations

[1 ]Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan; abby-eve@ 123456hotmail.com

[2 ]Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan

[3 ]Institute of Biopharmaceutical Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan; jjjaannee@ 123456hotmail.com

[4 ]Faculty of Pharmacy, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan

[5 ]School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan

[6 ]Department of Medical Research, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan

[7 ]National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan

Author notes

[* ]Correspondence: cyliu3@ 123456gmail.com (C.-Y.L.); cwshiau@ 123456ym.edu.tw (C.-W.S.); kfchen1970@ 123456ntu.edu.tw (K.-F.C.); Tel.: +886-2-2875-7529 (C.-Y.L.); +886-2-2826-7000 (ext. 7930) (C.-W.S.); +886-2-2312-3456 (ext. 63548) (K.-F.C.); Fax: +886-2-2875-7762 (C.-Y.L.); +886-2-2825-0883 (C.-W.S.); +886-2-2322-5329 (K.-F.C.)

Article

Publisher ID: ijms-18-01234

DOI: 10.3390/ijms18061234

PMC ID: 5486057

PubMed ID: 28594363

SO-VID: bb628827-a9f1-43e7-951d-24e0af9aeb6a

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 02 May 2017

Date accepted : 05 June 2017

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Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

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Neuronal Signaling

Most cited references 114

Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.

Protein-tyrosine phosphatases and cancer.

Strategies and Approaches of Targeting STAT3 for Cancer Treatment.

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