Linagliptin synergizes with cPLA2 inhibition to enhance temozolomide efficacy by interrupting DPP4-mediated EGFR stabilization in glioma.
10.1016/j.apsb.2025.05.012
- Author:
Dongyuan SU
1
;
Biao HONG
1
;
Shixue YANG
1
;
Jixing ZHAO
1
;
Xiaoteng CUI
1
;
Qi ZHAN
1
;
Kaikai YI
2
;
Yanping HUANG
1
;
Jiasheng JU
1
;
Eryan YANG
3
;
Qixue WANG
1
;
Junhu ZHOU
1
;
Yunfei WANG
1
;
Xing LIU
4
;
Chunsheng KANG
1
Author Information
1. Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
2. Department of Neuro-Oncology and Neurosurgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
3. Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin 300052, China.
4. Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China.
- Publication Type:Journal Article
- Keywords:
DPP4;
EGFR;
Glioblastoma;
Linagliptin;
Lipid remodeling;
Novel therapy;
PTRF;
cPLA2
- From:
Acta Pharmaceutica Sinica B
2025;15(7):3632-3645
- CountryChina
- Language:English
-
Abstract:
The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.
