Farnesoid X receptor induces cell death and sensitizes to TRAIL-induced inhibition of growth in colorectal cancer cells through the up-regulation of death receptor 5.

Abstract

Farnesoid X receptor (FXR) exhibits critical anti-cancer functions in several types of cancer, including colorectal cancer, in vitro and in vivo. However, the underlying mechanism remains unclear. We evaluated pharmacological activation of FXR with the synthetic agonist GW4064 using comprehensive proteomic analysis in colorectal cancer cell lines (HCT116, SW480, and DLD1). Among the commonly detected proteins in all three cell lines, death receptor 5 (DR5) was the most up-regulated protein, and key autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 alpha/beta (MLP3A/3B) and p62 sequestosome-1 (SQSTM), were also differentially expressed. Western blot analysis showed that GW4064 stimulation induced activation of the extrinsic death signaling pathway in all cell lines and induced activation of the intrinsic death signaling pathway in DLD1 cells. Western blotting showed that DR5 up-regulation was associated with inhibition of autophagic activity. These results suggest that FXR activation induced DR5 up-regulation through inhibition of autophagic activity and the DR5-related death signaling pathway. In addition, DR5 selective ligand, also known as TRAIL, has been widely used for anti-cancer treatment in several clinical trials. Co-treatment of TRAIL with GW4064 synergistically inhibited colorectal cancer cell proliferation as compared with single treatments. To the best of our knowledge, our results provide novel insights into FXR function in cancer cell lines. These findings may contribute to a new therapeutic strategy for colorectal cancer.

• Authors: Masahiro Hotta, Takashi Sakatani, Kousuke Ishino, Ryuichi Wada, Mitsuhiro Kudo, Yasuyuki Yokoyama, Takeshi Yamada, Hiroshi Yoshida, Zenya Naito
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 519 Issue 4 Pg. 824-831 (11 19 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 31561852 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Isoxazoles
• Receptors, Cytoplasmic and Nuclear
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• SQSTM1 protein, human
• Sequestosome-1 Protein
• TNF-Related Apoptosis-Inducing Ligand
• farnesoid X-activated receptor
• GW 4064

Topics

• Autophagy (drug effects, genetics)
• Cell Death (drug effects, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• HCT116 Cells
• Humans
• Isoxazoles (pharmacology)
• Proteomics (methods)
• Receptors, Cytoplasmic and Nuclear (agonists, genetics, metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Sequestosome-1 Protein (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Up-Regulation (drug effects)