Wnt/β-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer

Rao, Annavarapu Srinivas; Kremenevskaja, Natalia; Wasielewski, Reinhard von; Jakubcakova, Vladimira; Kant, Shashi; Resch, Julia; Brabant, Georg

doi:10.1210/jc.2005-1381

Cited by 37 publications

(18 citation statements)

References 41 publications

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“…Immunoblotting with c-Abl antibody revealed the presence of c-Abl protein in immunoprecipitated mixture as well as in immunoprecipitates with ß-catenin and TCF-4 antibody. ß-catenin and TCF-4 were used as positive control because their interactions with c-Abl have been established earlier [25, 26]. c-Abl was also found in immunoprecipitates from cells treated with lactose indicating that this interaction is not dependent on galectin’s carbohydrate-binding properties.…”

Section: Resultsmentioning

confidence: 93%

Galectin-3: A novel substrate for c-Abl kinase

Balan

Nangia‐Makker

Jung

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Galectin-3, a ß-galactoside-binding lectin, is found in cellular and extracellular location of the cell and has pleiotropic biological functions such as cell growth, cell adhesion and cell-cell interaction. It may exhibit anti or pro-apoptotic activity depending on its localization and post-translational modifications. Two important post-translational modifications of galectin-3 have been reported: its cleavage and phosphorylation. Cleavage of galectin-3 was reported to be involved with angiogenic potential and apoptotic resistance. Phosphorylation of galectin-3 regulates its sugar-binding ability. In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at position 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-Abl kinase. Tyrosine 107 is the main target of c-Abl. Expression of galectin-3 Y107F mutant in galectin-3 null SK-Br-3 cells leads to morphological changes and increased motility compared to wild type galectin-3. Further investigation is needed to better understand the functional significance of the novel tyrosine phosphorylated sites of galectin-3.

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Section: Resultsmentioning

confidence: 93%

Galectin-3: A novel substrate for c-Abl kinase

Balan

Nangia‐Makker

Jung

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Imatinib inhibited phosphorylation of c-ABL1, increased p21, decreased several cyclins, and increased cells in S phase (Podtcheko et al 2003) and also inhibited growth and induced apoptosis (Kurebayashi et al 2006). Reduced cell proliferation and the downstream Wnt/catenin (cadherin-associated protein), beta 1 pathway has been observed (Rao et al 2006). However, the drug may not achieve its effects at clinically achievable concentrations (Dziba & Ain 2004).…”

Section: Preclinical Studiesmentioning

confidence: 99%

Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies

Smallridge¹,

Marlow²,

Copland³

2009

Endocrine-Related Cancer

361

275

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Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of w 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.

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“…Imatinib mesylate inhibits tyrosine-phosphorylation of β-catenin (75), which may be one of the mechanisms for the chemopreventive effect of imatinib mesylate. However, imatinib mesylate has been reported to inhibit the Wnt/ β-catenin signaling in human colon cancer cell lines and thyroid carcinoma cell lines, suggesting that this chemical is also able to modulate the Wnt / β-catenin signaling (75).…”

Section: -3 Imatinib Mesylate and Othersmentioning

confidence: 99%

The Wnt/β-Catenin Signaling Pathway as a Target in Drug Discovery

2007

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Abstract. The cell signaling cascades provoked by Wnt proteins (the Wnt signaling pathways), which are well conserved through evolution, play crucial roles to maintain homeostasis of a variety of tissues such as skin, blood, intestine, and brain, as well as to regulate proliferation, morphology, motility, and fate of cells during embryonic development. Among these pathways, the signal transduction through β-catenin (the Wnt / β-catenin signaling pathway) has been most intensively studied because this signal regulates the expression of a number of genes essential for cell proliferation and differentiation and also this pathway is perturbed in a number of diseases such as cancers, bone diseases, and cardiovascular diseases. However, there is no therapeutic agents that can selectively modulate the Wnt / β-catenin signaling pathway, although some existing drugs (e.g., non-steroidal anti-inflammatory drugs, vitamins, and imatinib mesylate) have been suggested to inhibit this pathway. Here we provide an overview of the Wnt / β-catenin signaling pathway: its roles in physiology and pathology and the possibility as a target in development of new drugs.

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Wnt/β-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer

Abstract: Our data provide a molecular mechanism for the antitumor activity of imatinib that may help to develop it as a therapeutic option in a subset of ATC patients.

Cited by 37 publications

References 41 publications

Galectin-3: A novel substrate for c-Abl kinase

Galectin-3: A novel substrate for c-Abl kinase

Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies

The Wnt/β-Catenin Signaling Pathway as a Target in Drug Discovery

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