PKC–NF-κB are involved in CCL2-induced Nav1.8 expression and channel function in dorsal root ganglion neurons

Zhao, Rui; Pei, Guoxian; Cong, Rong; Zhang, Hang; Zang, Chengwu; Tian, Tong

doi:10.1042/bsr20140005

Cited by 29 publications

(28 citation statements)

References 24 publications

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“…To identify the downstream molecular mechanisms associated with CCL2/CCR2-mediated cell proliferation, we first examined expression of phosphorylated AKT, SMAD3, and ERK1/2 and PKC. These pathways were important in CCL2 signaling in neu-ronal cells and mediated survival and motility of prostate and mammary carcinoma cells (14,35,36). By immunoblot analysis, CCL2 treatment of MCF10CA1d cells increased phospho-PKC expression ( Fig.…”

Section: Ccl2/ccr2 Signaling Mediates Blbc Cell Growth Through Pkc Anmentioning

confidence: 89%

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

Yao

Fang

Smart

et al. 2019

Molecular Cancer Research

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Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor, and Her2 expression, and are resistant to antihormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage-dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal-like breast cancer, primary tumor growth was significantly increased with cotransplantation of patient-derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell-cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell-cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell-cycle inhibitor protein p27KIP1, and are necessary for CCL2-induced breast cancer cell proliferation.Implications: This report sheds novel light on CCL2/ CCR2 chemokine signaling as a mitogenic pathway and cell-cycle regulator in breast cancer cells.

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Section: Ccl2/ccr2 Signaling Mediates Blbc Cell Growth Through Pkc Anmentioning

confidence: 89%

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

Yao

Fang

Smart

et al. 2019

Molecular Cancer Research

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“…MCP-1 exposure has been shown to upregulate the neuronal expression of TRPV1 and NaV1.8 (Kao et al, 2012), potentially mediated by the activation of NFκB (Tse et al, 2014, Zhao et al, 2014). MCP-1 also enhances the sensitivity of sensory neurons as evidenced by an increase in nociceptive behaviors following hindpaw injection (Dansereau et al, 2008) and by a direct stimulation of CGRP release from cultures derived from neonatal DRG (Qin et al, 2005b).…”

Section: Discussionmentioning

confidence: 99%

DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1

et al. 2017

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Although inflammation-induced peripheral sensitization oftentimes resolves as an injury heals, this sensitization can be pathologically maintained and contribute to chronic inflammatory pain. Numerous inflammatory mediators increase the production of reactive oxygen (ROS) and nitrogen species (RNS) during inflammation and in animal models of chronic neuropathic pain. Our previous studies demonstrate that ROS/RNS and subsequent DNA damage mediate changes in neuronal sensitivity induced by anticancer drugs and by ionizing radiation in sensory neurons, thus we investigated whether inflammation and inflammatory mediators also could cause DNA damage in sensory neurons and whether that DNA damage alters neuronal sensitivity. DNA damage was assessed by pH2A.X expression and the release of the neuropeptide, calcitonin gene-related peptide (CGRP), was measured as an index of neuronal sensitivity. Peripheral inflammation or exposure of cultured sensory neurons to the inflammatory mediators, LPS and MCP-1, elicited DNA damage. Moreover, exposure of sensory neuronal cultures to LPS or MCP-1 resulted in changes in the stimulated release of CGRP, without altering resting release or CGRP content. Genetically enhancing the expression of the DNA repair enzyme, apurinic/apyrimidinic endonuclease (APE1) or treatment with a small-molecule modulator of APE1 DNA repair activity, both which enhance DNA repair, attenuated DNA damage and the changes in neuronal sensitivity elicited by LPS or MCP-1. In conclusion, our studies demonstrate that inflammation or exposure to inflammatory mediators elicits DNA damage in sensory neurons. By enhancing DNA repair, we demonstrate that this DNA damage mediates the alteration of neuronal function induced by inflammatory mediators in peptidergic sensory neurons.

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“…The nociceptive neurons of the DRG must not be discounted in their ability to generate aberrant sensory behavior, as these nociceptors exhibit increased spontaneous activity, likely amplifying neuropathic signaling(5). Nociceptor spontaneous activity may be amplified is through an increased macrophage presence and elevated proinflammatory cytokine levels in the DRG after injury (65-69). After SCI macrophages recruited to DRGs within a week of injury persist chronically (70).…”

Section: Discussionmentioning

confidence: 99%

Delayed Exercise Is Ineffective at Reversing Aberrant Nociceptive Afferent Plasticity or Neuropathic Pain After Spinal Cord Injury in Rats

Detloff

Quiros-Molina

Javia

et al. 2015

Neurorehabil Neural Repair

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Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that correlates with sensory fiber sprouting. Recent data indicates that exercise initiated early after SCI prevents the development of allodynia and modulated nociceptive afferent plasticity. This study determined if delaying exercise intervention until pain is detected would similarly ameliorate established SCI-induced pain. Adult, female Sprague-Dawley rats with a C5 unilateral contusion were separated into SCI allodynic and SCI non-allodynic cohorts at 14 or 28 dpi when half of each group began exercising on automated running wheels. Allodynia, assessed by von Frey testing, was not ameliorated by exercise. Furthermore, rats that began exercise with no allodynia developed paw hypersensitivity within 2 weeks. At the initiation of exercise, the SCI Allodynia group displayed marked overlap of peptidergic and non-peptidergic nociceptive afferents in the C7 and L5 dorsal horn, while the SCI No Allodynia group had scant overlap. At the end of 5 weeks of exercise both the SCI Allodynia and SCI No Allodynia group had extensive overlap of the 2 c fiber types. Our findings show that exercise therapy initiated at early stages of allodynia is ineffective at attenuating neuropathic pain, but rather that it induces allodynia aberrant afferent plasticity in previously pain-free rats. These data, combined with our previous results suggest that there is a critical therapeutic window when exercise therapy may be effective at treating SCI-induced allodynia and that there are post-injury periods when exercise can be deleterious.

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PKC–NF-κB are involved in CCL2-induced Nav1.8 expression and channel function in dorsal root ganglion neurons

Cited by 29 publications

References 24 publications

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1

Delayed Exercise Is Ineffective at Reversing Aberrant Nociceptive Afferent Plasticity or Neuropathic Pain After Spinal Cord Injury in Rats

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