Divergent Roles of PIK3C3 in KRAS-Wild-Type and KRAS-Mutant Advanced Colorectal Cancer: Implications for 5-Fluorouracil Sensitivity and Prognosis.
11 affiliations
- 1Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- 2Department of Pathology, School of Medicine, China Medical University, Taichung, Taiwan.
- 3Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan.
- 4Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan.
- 5Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- 6Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- 7Institute of Medical Informatics, College of Electrical Engineering and Computer Science, National Cheng Kung University, Tainan, Taiwan.
- 8Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- 9National Department of Food Safety/Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- 10National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
- 11Department of Pathology, National Cheng Kung University Hospital, Dou-Liou Branch, Douliu City, Yunlin County, Taiwan.
Abstract
Introduction
Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) is central to autophagy, which supports cancer adaptation to environmental stresses and may contribute to drug resistance. KRAS-mutant cancers have been reported to require autophagy for survival. We investigated the influence of KRAS mutation status on the roles of PIK3C3 in colorectal cancer (CRC) cell viability and chemosensitivity in vitro, as well as its association with patient prognosis.Methods
The clinical significance of PIK3C3 expression in relation to KRAS mutation status was evaluated by immunohistochemistry in patients with advanced CRC. Cell viability, colony formation, and spheroid formation assays were performed using CRC cell lines.Results
In KRAS-wild-type (KRAS-WT) Caco-2 and Colo320 cells, PIK3C3 and the KRAS/ERK pathway appeared to positively regulate each other. In contrast, PIK3C3 inhibition did not reduce p-ERK levels or induce significant p62 accumulation in KRAS-mutant SW480 and HCT116 cells. PIK3C3 knockdown reduced cell viability but increased resistance to 5-fluorouracil (5-FU) in Caco-2 and Colo320 cells, whereas the opposite effect was observed in SW480 and HCT116 cells. Transfection with a KRAS-mutant plasmid sensitized Caco-2 cells to 5-FU accompanied by reduced thymidylate synthase (TS) and β-catenin levels following PIK3C3 inhibition. Clinically, high PIK3C3 expression was associated with KRAS mutation and poorer survival in patients with advanced CRC. Its adverse short-term prognostic association was more pronounced in KRAS-mutant CRC than in KRAS-WT CRC.Conclusion
Based on preclinical in vitro findings, PIK3C3 appears to support KRAS-WT and KRAS-mutant CRCs in different ways. Notably, PIK3C3 inhibition enhances 5-FU sensitivity in KRAS-mutant CRC cells, potentially through TS regulation, and warrants further investigation as a therapeutic strategy.
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BibTeX
@article{chu2026divergent,
title = {{Divergent Roles of PIK3C3 in KRAS-Wild-Type and KRAS-Mutant Advanced Colorectal Cancer: Implications for 5-Fluorouracil Sensitivity and Prognosis.}},
author = {Chien-An Chu and Nan-Haw Chow and Jiu-Yao Wang and Chen Chang and Peng-Chan Lin and Yu-Min Yeh and Bo-Wen Lin and Yi-Wen Wang and Yun-Hao Dai and Yi-Lin Chen and Po-Chuan Chen and Shang-Hung Chen and Ren-Hao Chan and Chung-Liang Ho and Che-Wei Hsu and Chung-Ta Lee},
journal = {Cancer medicine},
year = {2026},
month = oct,
doi = {10.1002/cam4.72434},
url = {https://europepmc.org/article/MED/42958604},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Divergent Roles of PIK3C3 in KRAS-Wild-Type and KRAS-Mutant Advanced Colorectal Cancer: Implications for 5-Fluorouracil Sensitivity and Prognosis.
AU - Chien-An Chu
AU - Nan-Haw Chow
AU - Jiu-Yao Wang
AU - Chen Chang
AU - Peng-Chan Lin
AU - Yu-Min Yeh
AU - Bo-Wen Lin
AU - Yi-Wen Wang
AU - Yun-Hao Dai
AU - Yi-Lin Chen
AU - Po-Chuan Chen
AU - Shang-Hung Chen
AU - Ren-Hao Chan
AU - Chung-Liang Ho
AU - Che-Wei Hsu
AU - Chung-Ta Lee
PY - 2026
DA - 2026/10/29
JO - Cancer medicine
DO - 10.1002/cam4.72434
UR - https://europepmc.org/article/MED/42958604
AB - Introduction Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) is central to autophagy, which supports cancer adaptation to environmental stresses and may contribute to drug resistance. KRAS-mutant cancers have been reported to require autophagy for survival. We investigated the influence of KRAS mutation status on the roles of PIK3C3 in colorectal cancer (CRC) cell viability and chemosensitivity in vitro, as well as its association with patient prognosis.Methods The clinical significance of PIK3C3 expression in relation to KRAS mutation status was evaluated by immunohistochemistry in patients with advanced CRC. Cell viability, colony formation, and spheroid formation assays were performed using CRC cell lines.Results In KRAS-wild-type (KRAS-WT) Caco-2 and Colo320 cells, PIK3C3 and the KRAS/ERK pathway appeared to positively regulate each other. In contrast, PIK3C3 inhibition did not reduce p-ERK levels or induce significant p62 accumulation in KRAS-mutant SW480 and HCT116 cells. PIK3C3 knockdown reduced cell viability but increased resistance to 5-fluorouracil (5-FU) in Caco-2 and Colo320 cells, whereas the opposite effect was observed in SW480 and HCT116 cells. Transfection with a KRAS-mutant plasmid sensitized Caco-2 cells to 5-FU accompanied by reduced thymidylate synthase (TS) and β-catenin levels following PIK3C3 inhibition. Clinically, high PIK3C3 expression was associated with KRAS mutation and poorer survival in patients with advanced CRC. Its adverse short-term prognostic association was more pronounced in KRAS-mutant CRC than in KRAS-WT CRC.Conclusion Based on preclinical in vitro findings, PIK3C3 appears to support KRAS-WT and KRAS-mutant CRCs in different ways. Notably, PIK3C3 inhibition enhances 5-FU sensitivity in KRAS-mutant CRC cells, potentially through TS regulation, and warrants further investigation as a therapeutic strategy.
SN - 2045-7634
ER -