Guggulsterone inhibits migration and invasion through proteasomal and lysosomal degradation in human glioblastoma cells

Jen-Fu Yang; Tzu-Min Chen; Hsin-Han Chang; Yu-Ling Tsai; Wen-Chiuan Tsai; Wen-Yen Huang; Cheng-Hsiang Lo; Chun-Shu Lin; Po-Chien Shen; Ying Chen

doi:10.1016/j.ejphar.2022.175411

Guggulsterone inhibits migration and invasion through proteasomal and lysosomal degradation in human glioblastoma cells

Eur J Pharmacol. 2023 Jan 5:938:175411. doi: 10.1016/j.ejphar.2022.175411. Epub 2022 Nov 24.

Authors

Affiliations

¹ Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
² Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
³ Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁴ Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
⁵ Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
⁶ Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan. Electronic address: ychen0523@mail.ndmctsgh.edu.tw.

PMID: 36436590
DOI: 10.1016/j.ejphar.2022.175411

Abstract

Glioblastoma multiforme (GBM) is a deadly brain malignancy, and current therapies offer limited survival benefit. The phytosterol guggulsterone (GS) has been shown to exhibit antitumor efficacy. This study aimed to investigate the effects of GS on migration and invasion and its underlying mechanisms in human GBM cell lines. After GS treatment, the survival rate of GBM cells was reduced, and the migration and invasion abilities of GBM cells were significantly decreased. There was also concomitant decreased expression of focal adhesion complex, matrix metalloproteinase-2 (MMP2), MMP9 and cathepsin B. Furthermore, GS induced ERK phosphorylation and autophagy, with increased p62 and LC3B-II expression. Notably, treatment of in GBM cells with the proteasome inhibitor MG132 or the lysosome inhibitor NH₄Cl reversed the GS-mediated inhibition of migration and invasion. In an orthotopic xenograft mouse model, immunohistochemical staining of brain tumor tissues demonstrated that MMP2 and cathepsin B expression was reduced in GS-treated mice. GS treatment inhibited GBM cell migration and invasion via proteasomal and lysosomal degradation, suggesting its therapeutic potential in clinical use in the future.

Keywords: Autophagy; Glioblastoma; Guggulsterone; Invasion; Migration; Protein degradation.

MeSH terms

Animals
Brain Neoplasms* / pathology
Cathepsin B
Cell Line, Tumor
Cell Movement
Glioblastoma* / pathology
Humans
Lysosomes / metabolism
Matrix Metalloproteinase 2 / metabolism
Mice
Neoplasm Invasiveness
Proteasome Endopeptidase Complex / metabolism

Substances

Matrix Metalloproteinase 2
Cathepsin B
pregna-4,17-diene-3,16-dione
Proteasome Endopeptidase Complex