The anticancer antibiotic mithramycin-A inhibits TRPV1 expression in dorsal root ganglion neurons

Zavala, Kathryn; Lee, J.; Chong, J.; Sharma, Manohar; Eilers, Helge; Schumacher, Mark

doi:10.1016/j.neulet.2014.01.021

Cited by 14 publications

(16 citation statements)

References 33 publications

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“…2B and supplemental Table S1). Furthermore, several protein bands are in the predicted or previously observed molecular weight ranges for TRPV1; however, in comparison with ECs, some of these are not highly expressed in PBMCs (59,60). Taken together, the results from our CBR expression studies indicate that ECs express CB 1 R, GPR18, GPR55, and TRPV1 and possibly CB 2 R at very low levels.…”

Section: Endothelial Cells From Different Vascular Beds Express a Simsupporting

confidence: 58%

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

Wilhelmsen

Khakpour

Tran

et al. 2014

Journal of Biological Chemistry

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Background:The endothelium is centrally involved in acute inflammatory disorders. Results: WIN55,212-2 and the endocannabinoid N-arachidonoyl dopamine (NADA), but not anandamide nor 2-arachidonoylglycerol, reduce endothelial activation by bacterial Toll-like receptor agonists and TNF␣. Conclusion: NADA is a newly identified endogenous regulator of endothelial inflammation. Significance: The endothelial endocannabinoid system represents a novel immune regulatory system that could be exploited therapeutically.

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Section: Endothelial Cells From Different Vascular Beds Express a Simsupporting

confidence: 58%

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

Wilhelmsen

Khakpour

Tran

et al. 2014

Journal of Biological Chemistry

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“…Primary DRG neuronal cultures were derived from 6 to 8 week-old Sp4+/- and wt. mice using previous methods described [55, 56].…”

Section: Methodsmentioning

confidence: 99%

“…mice was accomplished by plating DRG neurons on coverslips coated with poly-DL-ornithine / laminin and preloaded with the calcium dye, Fura-2 AM (Invitrogen, Carlsbad, CA), for 40 min at 37°C (2.5 μM Fura-2 in HBSS + 20 mM HEPES + 0.1% BSA). DRG neurons were visualized through a motorized Axiovert 200 microscope (Carl Zeiss Light Microscopy, Germany) equipped with an ICCD camera (Stanford Photonics, Stanford, CA) and controlled through the Imaging Workbench software package (Indec Biosystems, Mountain View, CA) as previously described [56].…”

Section: Methodsmentioning

confidence: 99%

“…Using the StepOnePlus Real-Time PCR system (Applied Biosystems, Carlsbad, CA), cDNA samples were probed with the following primers: (Applied Biosystems-ABI) Sp4 (Cat# Hs00162095_ml), Sp1 F: ; R: [57], Sp3 F: ; R: [58], custom primers (Invitrogen (Life Technologies) TRPV1 F: ; R: ; TRPA1 F: ; R: ; TRPM8 F: ; R: ; ASIC3 F: ; R: [59]; TRPV4 F: ; R: [60]; Piezo1 F: ; R: [61]; Piezo2 F: ; R: [61]; TREK-1 F: ; R: [62]; TMEM150c F: ; R: [63]. The mRNA expression levels of the genes analyzed were normalized by GAPDH expression F: ; R: and represented as Relative Quantitation (RQ) using the comparative C T method as previously reported [18, 56, 64]…”

Section: Methodsmentioning

confidence: 99%

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Transcription factor Sp4 is required for hyperalgesic state persistence

et al. 2019

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Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist—capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.

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“…Sp1 has been demonstrated to be a transcription factor responsible for TRPV1 gene expression [37, 38] and constitutively overexpressed in MM cells [39–41]. Because activation of the PI3K/Akt pathway has been shown to induce nuclear localization of Sp1 in other types of cells [42–44], we next looked at nuclear localization of Sp1 in MM cells.…”

Section: Resultsmentioning

confidence: 99%

A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration

et al. 2016

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Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.

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The anticancer antibiotic mithramycin-A inhibits TRPV1 expression in dorsal root ganglion neurons

Cited by 14 publications

References 33 publications

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

Transcription factor Sp4 is required for hyperalgesic state persistence

A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration

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