Pharmacological inhibition of TFF3 enhances sensitivity of CMS4 colorectal carcinoma to 5-fluorouracil through inhibition of p44/42 MAPK

Ru Mei Chen, Yi Shiou Chiou, Qing Yun Chong, Han Ming Poh, Tuan Zea Tan, Meng Yi Zhang, Lan Ma, Tao Zhu, Vijay Pandey, Basappa Salundi, Alan Prem Kumar, Peter E. Lobie

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor—2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5Hpyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.

Original languageEnglish (US)
Article number6215
JournalInternational journal of molecular sciences
Volume20
Issue number24
DOIs
StatePublished - Dec 2 2019

Keywords

  • 5-FU
  • CMS4 CRC
  • Cancer stem cell
  • ERK1/2
  • Targeted therapy
  • Trefoil factor 3

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'Pharmacological inhibition of TFF3 enhances sensitivity of CMS4 colorectal carcinoma to 5-fluorouracil through inhibition of p44/42 MAPK'. Together they form a unique fingerprint.

Cite this