S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase

Che, Pulin; Yang, Youfeng; Han, Xiaosi; Meng, Heng; Sellers, Jeffrey C.; Londoño-Joshi, Angelina I.; Cai, Guoqiang; Buchsbaum, Donald J.; Christein, John D.; Tang, Qinjiu; Chen, Dongquan; Li, Qianjun; Grizzle, William E.; Yin, Lu; Ding, Qiang

doi:10.1038/srep08453

Cited by 43 publications

(44 citation statements)

References 56 publications

(99 reference statements)

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“…In contrast, FAK Tyr397 phosphorylation was significantly decreased by bosutinib in thyroid cancer (30). Another Src/Abl inhibitor dasatinib also inhibited FAK Tyr397 phosphorylation in colon cancer and pancreatic cancer (31,32). The precise molecular mechanisms for these conflicting results need to be investigated further to determine how to abrogate the downstream signaling pathways of Src using Src inhibitors more effectively.…”

Section: Discussionmentioning

confidence: 99%

Src as a Therapeutic Target in Biliary Tract Cancer

Nam

Kim

Park

et al. 2016

Molecular Cancer Therapeutics

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Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G 1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects.In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515-24. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Src as a Therapeutic Target in Biliary Tract Cancer

Nam

Kim

Park

et al. 2016

Molecular Cancer Therapeutics

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“…The TNF-α ARE (nucleotides 1221 to 1310; GenBank accession no. M10988) was then inserted between EcoRV and HindIII sites and infected cells as described previously by us [37;38]. …”

Section: Methodsmentioning

confidence: 99%

Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism

et al. 2016

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RationaleTumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory mediator and its expression is up-regulated in chronic obstructive pulmonary disease (COPD). Tristetraprolin (TTP) is implicated in regulation of TNF-α expression; however, whether TTP is involved in cigarette smoke-induced TNF-α expression has not been determined.MethodsTTP expression was examined by western blot analysis in murine alveolar macrophages and alveolar epithelial cells challenged without or with cigarette smoke extract (CSE). TNF-α mRNA stability, and the decay of TNF-α mRNA, were determined by real-time quantitative RT-PCR. TNF-α protein levels were examined at the same time in these cells. To identify the molecular mechanism involved, a construct expressing the human beta-globin reporter mRNA containing the TNF-α 3’-untranslated region was generated to characterize the TTP targeted site within TNF-α mRNA.ResultsCSE induced TTP down-regulation in alveolar macrophages and alveolar epithelial cells. Reduced TTP expression resulted in significantly increased TNF-α mRNA stability. Importantly, increased TNF-α mRNA stability due to impaired TTP function resulted in significantly increased TNF-α levels in these cells. Forced TTP expression abrogated the increased TNF-α mRNA stability and expression induced by CSE. By using the globin reporter construct containing TNF-α mRNA 3’-untranslated region, the data indicate that TTP directly targets the adenine- and uridine-rich region (ARE) of TNF-α mRNA and negatively regulates TNF-α expression at the post-transcriptional level.ConclusionThe data demonstrate that cigarette smoke exposure reduces TTP expression and impairs TTP function, resulting in significantly increased TNF-α mRNA stability and excessive TNF-α expression in alveolar macrophages and epithelial cells. The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-α expression and inflammatory response induced by cigarette smoke.

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“…Several studies showed S100A4 to be protective against pro-apoptotic stimuli [96][97][98]. Orre et al [99] showed that S100A4 interacts with the tumor suppressor p53 in the nucleus and promotes p53 degradation.…”

Section: Wnt Signaling Target: S100a4mentioning

confidence: 99%

Underlying Mechanisms for Distant Metastasis - Molecular Biology

2017

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Concepts of MetastasisIn 1889, the English surgeon Stephen Paget illustrated his theory on metastasis with the sentence 'When a plant goes to seed, its seeds are carried in all directions, but they can only live and grow if they fall on congenial soil'. He based this 'seed and soil' hypothesis on autopsy records where he detected a discrepancy between the blood supply and frequency of metastasis in specific organs. He concluded that the development of metastasis depends on distinctive features of the tumor cells as well as the specific target organs [1,2]. This concept replaced the mechanistic hypothesis of Rudolf Virchow who considered metastasis as the arrest of tumor cell emboli in the vasculature [2]. Nowadays, metastasis is understood as a complex process of molecular and biochemical events performed by multiple actors. The concept of a 'homogenous seed' has been replaced by a heterogeneous hierarchically organized system of tumorigenic cancer stem cells and their non-tumorigenic progeny [3]. Cancer stem cells are now regarded to be the major driver in metastasis development. In addition, the idea of a sequential development of a cancer from a single primary tumor to the subsequent spread to distant sites was abandoned in the last years and replaced by a model of a simultaneous progression towards metastatic tumor disease. The currently favored model describes the evolution of systemic tumor disease as a parallel development of primary tumor and distant metastasis caused by heterogeneous tumor subpopulations [4].To understand the cellular and molecular basis of metastasis, the most acknowledged approach is the concept of the invasionmetastasis cascade proposed by Isaiah J. Fidler in 2003 and subsequently adapted by Scott Valastyan in 2011 [5,6]. The authors distinguish 6 steps in the process from primary local tumor to distant Keywords Metastasis · Molecular mechanism · Cancer therapy Summary Background:The formation of distant metastases constitutes a complex process with a variety of different genes and pathways involved. To improve patient survival, it is necessary to understand the underlying mechanisms of metastasis to allow for targeted intervention. Methods: This review provides an overview of the general concepts of metastasis, focusing on the most important genes and pathways involved and on interventional strategies. Results: Cancer cells undergo different steps to form metastasis: most prominently, local invasion, intravasation, survival in the circulation, arrest at a distant organ site and extravasation, micrometastasis formation, and metastatic colonization. In order to pass these steps, different molecular pathways are of major importance: EGF/RAS/ RAF/MEK/ERK, PI3K/Akt/mTOR, HGF/Met, Wnt/ -catenin, and VEGF signaling. The HGF/Met regulator MACC1 and the Wnt signaling target S100A4 have been shown to play a major role in the metastatic process. Each gene and pathway provides an opportunity for therapeutic intervention. Conclusion: Since metastasis represents a highly limiting factor in cancer...

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S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase

Cited by 43 publications

References 56 publications

Src as a Therapeutic Target in Biliary Tract Cancer

Src as a Therapeutic Target in Biliary Tract Cancer

Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism

Underlying Mechanisms for Distant Metastasis - Molecular Biology

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