FNDC5 enhances quercetin-induced anoikis in pancreatic adenocarcinoma cells via focal adhesion kinase-dependent mechanisms

doi:10.4251/wjgo.v18.i5.118849

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May 15, 2026 (publication date) through May 14, 2026

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World Journal of Gastrointestinal Oncology

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1948-5204

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. May 15, 2026; 18(5): 118849
Published online May 15, 2026. doi: 10.4251/wjgo.v18.i5.118849

FNDC5 enhances quercetin-induced anoikis in pancreatic adenocarcinoma cells via focal adhesion kinase-dependent mechanisms

Hui-Feng Gao, Ke Zhang, Chien-Shan Cheng, Ye-Hua Shen, Hao Chen

Hui-Feng Gao, Ke Zhang, Chien-Shan Cheng, Ye-Hua Shen, Hao Chen, Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

Hui-Feng Gao, Ke Zhang, Chien-Shan Cheng, Ye-Hua Shen, Hao Chen, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Co-corresponding authors: Ye-Hua Shen and Hao Chen.

Author contributions: Gao HF and Zhang K designed the study; Cheng CS and Shen YH performed the experiments; Shen YH and Chen H served as co-corresponding authors and jointly analyzed the data and edited the manuscript; all authors contributed to editorial changes in the manuscript, read and approved the final manuscript.

Supported by the National Natural Science Foundation of China, No. 82074204.

Institutional animal care and use committee statement: All experimental protocols in this study were carried out exclusively with cell lines, and therefore no experiments involving animal subjects were required.

Conflict-of-interest statement: The authors declare that they have no competing interests.

Data sharing statement: No additional data are available.

Corresponding author: Hao Chen, MD, Chief Physician, Department of Integrative Oncology, Fudan University Shanghai Cancer Center, No. 270 Dong’an Road, Shanghai 200032, China. chengkll@sina.com

Received: January 27, 2026
Revised: February 26, 2026
Accepted: March 23, 2026
Published online: May 15, 2026
Processing time: 106 Days and 17 Hours

Abstract

BACKGROUND

The role of FNDC5/irisin in regulating sensitivity to pancreatic ductal adenocarcinoma (PAAD) chemotherapy remains unclear.

AIM

To explore the role of FNDC5/irisin in regulating sensitivity to PAAD chemotherapy.

METHODS

The prognostic significance of FNDC5 was analyzed using bioinformatics. PAAD cells with FNDC5 overexpression, treated with quercetin, and control cells were compared in vitro. Cell proliferation was measured by real-time cellular analysis and colony formation assays, while apoptosis and anoikis were assessed flow cytometry. Protein expression was determined by western blotting, gene expression was determined by real-time quantitative polymerase chain reaction, and mitochondrial membrane potential was determined using the JC-1 method.

RESULTS

FNDC5 expression correlated with a good prognosis of PAAD. Overexpression of FNDC5 significantly enhanced the tumoricidal effects of quercetin, as evidenced by reduced proliferation and increased apoptosis and anoikis. Mechanistically, FNDC5 suppressed the focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase/protein kinase B pathway, leading to mitochondrial-dependent apoptosis and anoikis through modulation of apoptosis-related proteins.

CONCLUSION

Our findings suggest that the FNDC5/FAK axis as a novel regulator of anoikis sensitivity in PAAD. Targeting this axis may represent a promising strategy to enhance the efficacy of quercetin and other natural compounds, offering a potential therapeutic approach to overcome chemoresistance in this aggressive malignancy.

Keywords: FNDC5; Irisin; Quercetin; Pancreatic ductal adenocarcinoma; Anoikis; Focal adhesion kinase; Mitochondrial apoptosis; Chemosensitivity

Core Tip: This study highlights that FNDC5 enhances quercetin-mediated growth inhibition, apoptosis, and anoikis through focal adhesion kinase/phosphatidylinositol 3-kinase/protein kinase B inhibition and mitochondrial apoptosis initiation. Our results provide further insight into the effect of irisin on pancreatic ductal adenocarcinoma (PAAD) cells and suggest a new strategy for PAAD treatment that combines quercetin and irisin.