Src as the link between inflammation and cancer

Liu, Sandy; Pham, Hung; Pandol, Stephen J.; Ptasznik, Andrzej

doi:10.3389/fphys.2013.00416

Cited by 58 publications

(56 citation statements)

References 73 publications

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“…The development of Src inhibitors for cancer treatment had been carried on for decades (Lowell, 2004). As recent studies found that both tumor cells and tumor-infiltrating immune cells utilize Src to facilitate cancer development and progression (Liu et al, 2014), to some extent, the role that Src inhibitors played in cancer treatment may be attributed to their regulation of inflammation. Hence, clinical data on the use of Src inhibitors in cancer treatment may also provide strong support for their potential application on neuroinflammation-related diseases.…”

Section: Discussionmentioning

confidence: 99%

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

et al. 2020

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Chronic neuroinflammation is of great importance in the pathogenesis of Parkinson's disease (PD). During the process of neuroinflammation, overactivated microglia release many proinflammatory factors, which eventually induce neurodegeneration. Inhibition of excessive microglial activation is regarded as a promising strategy for PD treatment. Src is a non-receptor tyrosine kinase that is closely related to tumors. Recently, some reports indicated that Src is a central mediator in multiple signaling pathways including neuroinflammation. The aim of our study was to demonstrate the role of Src in microglial regulation and neuroinflammation. The lipopolysaccharide (LPS)-stimulated BV2 microglia model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced PD model were applied in this study. The results showed that inhibition of Src could significantly relieve microgliosis and decrease levels of inflammatory factors. Besides, inhibition of Src function reduced the loss of dopaminergic neurons and improved the motor behavior of the MPTP-treated mice. Thus, this study not only verified the critical role of Src tyrosine kinase in neuroinflammation but also further proved that interfering neuroinflammation is beneficial for PD treatment. More importantly, this study shed a light on the hypothesis that Src tyrosine kinase might be a potential therapeutic target for PD and other neuroinflammation-related diseases.

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Section: Discussionmentioning

confidence: 99%

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

et al. 2020

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“…Chronic pancreatitis involves long-standing inflammation of the pancreas associated with an increased risk (20 folds) for pancreatic cancer. 32 PP2A is a key Ser/Thr phosphatase responsible for dephosphorylating of a wide array of signaling molecules and it responds to inflammatory stimulation. Transforming growth factor-b (TGF-b), a major profibrotic cytokine implicated in scleroderma fibrosis, down-regulates PP2Ac expression in fibroblasts, resulting in ERK phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

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Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

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“…Additionally, a high-fat diet could also promote inflammatory factors such as IL1-␤ and TNF-␣, among others. Src family kinases are essential nodes to mediate inflammatory factors (35,36). Elevated myristoylation promotes the activity of Src family kinases and accelerates the inflammatory response in cancer progression.…”

Section: Src Myristoylation-diet Interaction In Tumor Progressionmentioning

confidence: 99%

Myristoylation of Src kinase mediates Src-induced and high-fat diet–accelerated prostate tumor progression in mice

Kim

Yang

et al. 2017

Journal of Biological Chemistry

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Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression.

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Src as the link between inflammation and cancer

Cited by 58 publications

References 73 publications

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

Myristoylation of Src kinase mediates Src-induced and high-fat diet–accelerated prostate tumor progression in mice

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