Research Paper Volume 16, Issue 11 pp 9410—9436
APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer
- 1 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250023, China
- 2 Department of Oncology, Shandong Second Provincial General Hospital, Jinan 250023, China
- 3 China Key Laboratory of Marine Drugs, The Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
- 4 Department of Pathology, Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China
- 5 Department of Oncology, 960 Hospital of People’s Liberation Army, Jinan 250031, China
- 6 Department of Pathology, Navy 971 People’s Liberation Army Hospital, Qingdao 266071, China
Received: November 15, 2023 Accepted: March 25, 2024 Published: June 6, 2024
https://doi.org/10.18632/aging.205872How to Cite
Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
Abbreviations
CRC: Colorectal cancer; L-OHP: Oxaliplatin; PIK3CA: The phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; APOA5: Apolipoprotein A5; CSC: Cancer stem cell; CCK-8: Cell Counting Kit-8; IHC: Immunohistochemical staining; NAC: N-acetylcysteine; DFS: Disease-free survival; OS: Overall survival; ROS: Reactive oxygen species.