The Inhibition of Src Family Kinase Suppresses Pancreatic Cancer Cell Proliferation, Migration, and Invasion

Je, Dong Wook; O, Young Moon; Ji, Young Geon; Cho, Yunkyung; Lee, Dong Hyeon

doi:10.1097/mpa.0000000000000103

Cited by 63 publications

(63 citation statements)

References 41 publications

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“…Other studies have also reported on low FRK mRNA and associated protein levels in the glioma tissues compared to their non-tumourous brain counterparts [32]. FRK mRNA expression was also detected in the pancreatic cancer cell lines, PANC-1 and MIA PaCa [50]. In light of the latter, a recent report profiling the global methylation status of 807 genes in pancreatic cancer revealed FRK to be a hypomethylated gene [51].…”

Section: Cancer Cell Lines and Tissuesmentioning

confidence: 85%

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

Goel

Lukong

2016

Cancer Metastasis Rev

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The non-receptor tyrosine kinase Fyn-related kinase (FRK) is a member of the BRK family kinases (BFKs) and is distantly related to the Src family kinases (SFKs). FRK was first discovered in 1993, and studies pursued thereafter attributed a potential tumour-suppressive function to the enzyme. In recent years, however, further functional characterization of the tyrosine kinase in diverse cancer types suggests that FRK may potentially play an oncogenic role as well. Specifically, while ectopic expression of FRK suppresses cell proliferation and migration in breast and brain cancers, knockdown or catalytic inhibition of FRK suppresses these cellular processes in pancreatic and liver cancer. Such functional paradox is therefore evidently exhibited in a tissue-specific context. This review sheds light on the recent developments emerged from investigations on FRK which include: (a) a review of the expression pattern of the protein in mammalian cells/tissues, (b) underlying genomic perturbations and (c) a mechanistic function of the enzyme across different cellular environments. Given its functional heterogeneity observed across different cancers, we also discuss the therapeutic significance of FRK.

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Section: Cancer Cell Lines and Tissuesmentioning

confidence: 85%

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

Goel

Lukong

2016

Cancer Metastasis Rev

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“…Src deregulation primarily involves protein overexpression and abnormalities in Src kinase activity. Differences in Src expression have been observed in lung, breast, pancreatic, colon and prostate cancer cells, compared with normal adjacent tissue, fibroblasts or normal mucosal cells (26)(27)(28)(29)(30)(31). In the tumor microenvironment, Src activation has been observed in cancer and inflammatory cells, and may serve as a critical mechanistic link between inflammation and cancer.…”

Section: Functions Of Src In Cancermentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

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Abstract. Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

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“…The non-receptor tyrosine kinase Src regulates a number of signaling pathways that are involved in survival, adhesion, proliferation, invasion and migration [27, 28]. It has been shown that Src plays a critical role in regulating Rho GTPases such as Rac1, and one of the major functions of Src is to modulate the actin cytoskeleton that controls cell migration.…”

Section: Introductionmentioning

confidence: 99%

Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells

Li¹,

Zhou²,

Jiang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Pro-angiogenic factors VEGF and IL-8 play a major role in modulating the migratory potential of endothelial cells. The goal of this study was to investigate the effect of autocrine VEGF and IL-8 in the form of self-conditioned medium (CM) on human umbilical vein endothelial cells (HUVECs). Methods: Enzyme-linked immunosorbent assay (ELISA) examined the automatic secretion of VEGF and IL-8 protein by HUVECs. Western blot, small interfering RNA (siRNA), pulldown and Transwell assays were used to explore the role and the mechanism of autocrine VEGF and IL-8 in migration of HUVECs. Results: Neutralizing VEGF and IL-8 in CM significantly abrogated CM-induced migration of HUVECs. Autocrine VEGF and IL-8 increased Src phosphorylation, Rac1 activity and PAK1 phosphorylation in a time dependent manner. Additionally, blocking Rac1 activity with Rac1 siRNA largely abolished autocrine VEGF and IL-8-induced cell migration. Vav2 siRNA suppressed autocrine VEGF and IL-8-induced Rac1 activation and cell migration. Furthermore, blocking Src signaling with PP2, a specific inhibitor for Src, markedly prevented autocrine VEGF and IL-8-induced Vav2 and Rac1 activation as well as consequently cell migration. PAK1 siRNA also significantly abolished autocrine VEGF and IL-8-induced cell migration. Conclusions: We demonstrated for the first time that autocrine VEGF and IL-8 promoted endothelial cell migration via the Src/Vav2/Rac1/PAK1 signaling pathway. This finding reveals the molecular mechanism in the increase of endothelial cell migration induced by autocrine growth factors and cytokines, which is expected to provide a novel therapeutic target in vascular diseases.

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The Inhibition of Src Family Kinase Suppresses Pancreatic Cancer Cell Proliferation, Migration, and Invasion

Abstract: These results suggest that the knockdown of Yes1, Lyn, Fyn, Frk, or Src reduce human pancreatic cancer cell proliferation, migration, and invasion, and that SFKs should be viewed as critical therapeutic targets of pancreatic cancer.

Cited by 63 publications

References 41 publications

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

The importance of Src signaling in sarcoma

Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells

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