Pentagalloyl glucose targets the JAK1/JAK3-STAT3 pathway to inhibit cancer stem cells and epithelial-mesenchymal transition in 5-fluorouracil-resistant colorectal cancer.

Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2025 Jul; Vol. 142, pp. 156773. Date of Electronic Publication: 2025 Apr 16.

Competing Interests: Declaration of competing interest The authors declare that they have no financial interests or personal relationships that could have influenced the work presented in this study. Moreover, they declare that there is no conflict of interest exist.
Background: Colorectal cancer (CRC) resistance to 5-fluorouracil (5-FU), primarily driven by cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), remains a major clinical challenge, necessitating novel therapeutic strategies.
Purpose: This study aims to evaluate the therapeutic potential of pentagalloyl glucose (PGG), a bioactive compound derived from Bouea macrophylla seeds, in overcoming 5-FU resistance in CRC.
Method: Anti-tumor effects of PGG were investigated using two- and three-dimensional (2D and 3D) cell culture models and subcutaneous xenograft and metastatic mouse models. Transcriptome sequencing, western blotting, and pharmacological inhibitors were employed to elucidate the underlying molecular mechanisms.
Results: PGG demonstrated potent anti-CSC activity; suppressed EMT-driven invasion and metastasis; and induced apoptosis in 2D monolayers, 3D spheroid models, and xenograft tumor models. Mechanistically, PGG selectively inhibited the JAK1/JAK3-STAT3 signaling pathway, considerably reducing STAT3 phosphorylation. This disruption downregulated the expression of CSC markers (CD133 and CD44), EMT regulators (N-cadherin and vimentin), and anti-apoptotic proteins (Bcl-2), effectively sensitizing 5-FU-resistant CRC to therapy.
Conclusion: PGG inhibit dual-target of CSCs and EMT via JAK1/JAK3-STAT3 signaling pathway in 5-FU-resistant CRC, providing a novel therapeutic approach to overcome chemoresistance.
(Copyright © 2025 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

English

Publisher: Urban & Fischer Verlag Country of Publication: Germany NLM ID: 9438794 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1618-095X (Electronic) Linking ISSN: 09447113 NLM ISO Abbreviation: Phytomedicine Subsets: MEDLINE

Epithelial-Mesenchymal Transition*/drug effects , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/metabolism , Colorectal Neoplasms*/pathology , Neoplastic Stem Cells*/drug effects , Hydrolyzable Tannins*/pharmacology, Humans ; Fluorouracil/pharmacology ; Animals ; STAT3 Transcription Factor/metabolism ; Drug Resistance, Neoplasm/drug effects ; Mice ; Signal Transduction/drug effects ; Janus Kinase 1/metabolism ; Xenograft Model Antitumor Assays ; Janus Kinase 3/metabolism ; Cell Line, Tumor ; Mice, Nude ; Mice, Inbred BALB C ; Apoptosis/drug effects

20250526