The NR4A agonist, Cytosporone B, attenuates pro-inflammatory mediators in human colorectal cancer tissue ex vivo

Biochem Biophys Res Commun. 2021 May 21;554:179-185. doi: 10.1016/j.bbrc.2021.03.110. Epub 2021 Mar 30.

Abstract

Inflammation is a pivotal pathological factor in colorectal cancer (CRC) initiation and progression, and modulating this inflammatory state has the potential to ameliorate disease progression. NR4A receptors have emerged as key regulators of inflammatory pathways that are important in CRC. Here, we have examined the effect of NR4A agonist, Cytosporone B (CsnB), on colorectal tissue integrity and its effect on the inflammatory profile in CRC tissue ex vivo. Here, we demonstrate concentrations up 100 μM CsnB did not adversely affect tissue integrity as measured using transepithelial electrical resistance, histology and crypt height. Subsequently, we reveal through the use of a cytokine/chemokine array, ELISA and qRT-PCR analysis that multiple pro-inflammatory mediators were significantly increased in CRC tissue compared to control tissue, which were then attenuated with the addition of CsnB (such as IL-1β, IL-8 and TNFα). Lastly, stratification of the data revealed that CsnB especially alters the inflammatory profile of tumours derived from males who had not undergone chemoradiotherapy. Thus, this study demonstrates that NR4A agonist CsnB does not adversely affect colon tissue structure or functionality and can attenuate the pro-inflammatory state of human CRC tissue ex vivo.

Keywords: Colorectal cancer; Cytosporone B; Inflammation; NR4A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Chemokines / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Cytokines / metabolism
  • Female
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation Mediators / metabolism*
  • Male
  • Middle Aged
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / agonists*
  • Phenylacetates / pharmacology*

Substances

  • Chemokines
  • Cytokines
  • Inflammation Mediators
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates
  • cytosporone B