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Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines.

ABSTRACT: Osteosarcoma is a heterogeneous tumor intimately linked to its microenvironment, which promotes its growth and spread. It is generally accompanied by cancer-induced bone pain (CIBP), whose main component is neuropathic pain. The TRPA1 ion channel plays a key role in metastasis and is increasingly expressed in bone cancer. Here, a novel TRPA1 inhibitor is described and tested together with two other known TRPA1 antagonists. The novel lipoyl derivative has been successfully assessed for its ability to reduce human osteosarcoma MG-63 cell viability, motility, and gene expression of the CIBP pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). A putative three-dimensional (3D) model of the inhibitor covalently bound to TRPA1 is also proposed. The in vitro data suggest that the novel inhibitor described here may be highly interesting and stimulating for new strategies to treat osteosarcomas.

SUBMITTER: Francesconi O

PROVIDER: S-EPMC9667541 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines.

Francesconi Oscar O Corzana Francisco F Kontogianni Georgia-Ioanna GI Pesciullesi Giorgio G Gualdani Roberta R Supuran Claudiu T CT Angeli Andrea A Kavasi Rafaela Maria RM Chatzinikolaidou Maria M Nativi Cristina C

ACS pharmacology & translational science 20220913 11

Osteosarcoma is a heterogeneous tumor intimately linked to its microenvironment, which promotes its growth and spread. It is generally accompanied by cancer-induced bone pain (CIBP), whose main component is neuropathic pain. The TRPA1 ion channel plays a key role in metastasis and is increasingly expressed in bone cancer. Here, a novel TRPA1 inhibitor is described and tested together with two other known TRPA1 antagonists. The novel lipoyl derivative has been successfully assessed for its abilit ...[more]

PMID: 36407953

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Project description:BackgroundTransient receptor potential ankyrin 1 (TRPA1) channels are known to be actively involved in various pathophysiological conditions, including neuronal inflammation, neuropathic pain, and various immunological responses. Heat shock protein 90 (Hsp90), a cytoplasmic molecular chaperone, is well-reported for various cellular and physiological processes. Hsp90 inhibition by various molecules has garnered importance for its therapeutic significance in the downregulation of inflammation and are proposed as anti-cancer drugs. However, the possible role of TRPA1 in the Hsp90-associated modulation of immune responses remains scanty.ResultsHere, we have investigated the role of TRPA1 in regulating the anti-inflammatory effect of Hsp90 inhibition via 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) in lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) stimulation in RAW 264.7, a mouse macrophage cell lines and PMA differentiated THP-1, a human monocytic cell line similar to macrophages. Activation of TRPA1 with Allyl isothiocyanate (AITC) is observed to execute an anti-inflammatory role via augmenting Hsp90 inhibition-mediated anti-inflammatory responses towards LPS or PMA stimulation in macrophages, whereas inhibition of TRPA1 by 1,2,3,6-Tetrahydro-1,3-dimethyl-N-[4-(1-methylethyl)phenyl]-2,6-dioxo-7 H-purine-7-acetamide,2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7 H-purin-7-yl)-N-(4-isopropylphenyl)acetamide (HC-030031) downregulates these developments. LPS or PMA-induced macrophage activation was found to be regulated by TRPA1. The same was confirmed by studying the levels of activation markers (major histocompatibility complex II (MHCII), cluster of differentiation (CD) 80 (CD80), and CD86, pro-inflammatory cytokines (tumor necrosis factor (TNF) and interleukin 6 (IL-6)), NO (nitric oxide) production, differential expression of mitogen-activated protein kinase (MAPK) signaling pathways (p-p38 MAPK, phospho-extracellular signal-regulated kinase 1/2 (p-ERK 1/2), and phosphor-stress-activated protein kinase/c-Jun N-terminal kinase (p-SAPK/JNK)), and induction of apoptosis. Additionally, TRPA1 has been found to be an important contributor to intracellular calcium levels toward Hsp90 inhibition in LPS or PMA-stimulated macrophages.ConclusionThis study indicates a significant role of TRPA1 in Hsp90 inhibition-mediated anti-inflammatory developments in LPS or PMA-stimulated macrophages. Activation of TRPA1 and inhibition of Hsp90 has synergistic roles towards regulating inflammatory responses associated with macrophages. The role of TRPA1 in Hsp90 inhibition-mediated modulation of macrophage responses may provide insights towards designing future novel therapeutic approaches to regulate various inflammatory responses.

Dataset Information

Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines.

Publications

Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines.

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