Guggulsterone suppresses osteosarcoma progression by inhibiting glycolysis through MAPK signaling pathway

Abstract

Background: Osteosarcoma (OS) represents an aggressive primary cancer originating in bone. It is predominantly diagnosed in pediatric and young adult populations, constituting approximately 20 % of bone malignancies in these age groups. Treatment efficacy is often hampered by chemoresistance. Guggulsterone (GS), a plant-derived sterol from Commiphora wightii, demonstrates promising anti-tumor potential, yet its effects on OS remain unexplored.

Purpose: The objective of this research was to clarify the anti-cancer mechanisms through which GS acts in OS and to evaluate its therapeutic prospects, with a particular focus on its influence over glycolysis and related signaling pathways.

Methods: In vitro investigations involved assessing cell viability, colony formation capability, apoptosis via flow cytometry, migration using Transwell assays, and protein levels by Western blot. Transcriptomic changes were evaluated using RNA sequencing. The anti-tumor efficacy of GS in vivo was confirmed using xenograft tumor models.

Results: GS treatment led to a significant decrease in OS cell proliferation, induced cell cycle arrest at the G2/M phase, and promoted apoptosis. Furthermore, GS suppressed OS cell migration and invasion, concurrent with modulation of proteins related to epithelial-mesenchymal transition (EMT). Mechanistically, GS targeted the MAPK signaling pathway, which resulted in impaired glycolytic activity and altered cellular energy metabolism. In vivo, administration of GS curtailed tumor growth without inducing noticeable systemic toxicity.

Conclusion: GS effectively counteracts OS progression by inhibiting glycolysis through MAPK pathway suppression. These findings suggest GS represents a promising therapeutic avenue for OS treatment.

Keywords: Glycolysis; Guggulsterone; MAPK pathway; Osteosarcoma.