TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione

Morice, Alyn H.; Sadofsky, Laura R.; Benemei, Silvia; Coppi, Elisabetta; De Logu, Francesco; Di Tommaso, Mariarosaria; Fusi, Camilla; Geppetti, Pierangelo; Li Puma, Simone; Marone, Ilaria M.; Materazzi, Serena; Moneti, Gloriano; Nassini, Romina; Susini, Tommaso; Terreni, Alessandro; Tonello, Raquel

Abstract

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS.

Citation

Morice, A. H., Sadofsky, L. R., Benemei, S., Coppi, E., De Logu, F., Di Tommaso, M., …Tonello, R. (2016). TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione. Cancer Research, 76(23), 7024-7035. https://doi.org/10.1158/0008-5472.CAN-16-1492

• Acceptance Date: Sep 1, 2016
• Online Publication Date: Oct 6, 2016
• Publication Date: Dec 1, 2016
• Deposit Date: Feb 28, 2017
• Publicly Available Date: Feb 28, 2017
• Journal: Cancer research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 76
• Issue: 23
• Pages: 7024-7035
• DOI: https://doi.org/10.1158/0008-5472.CAN-16-1492
• Keywords: Pain and palliative care, Steroid hormones and receptors, Aromatase inhibitors, Androstenedione, TRPA1
• Public URL: https://hull-repository.worktribe.com/output/448985
• Publisher URL: http://cancerres.aacrjournals.org/content/76/23/7024.article-info
• PMID: 27758889
• Additional Information: Authors' accepted manuscript of article published in: Cancer research, 2017, v.76, issue 23.