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journal article·2025-10Open access

Contribution of Prostaglandin E2‐Induced Neuronal Excitation to Drug Resistance in Glioblastoma Countered by a Novel Blood–Brain Barrier Crossing Celecoxib Derivative

Chih‐Jie Shen, Hsien‐Chung Chen, Chien‐Liang Lin, Amandeep Thakur, Raphael Onuku, I‐Chung Chen, Hao‐Yi Li, Kwang‐Yu Chang, Jian‐Ying Chuang, Wen‐Bin Yang, Hong‐Yi Lin, Yi‐Ru Shen, Jing‐Ping Liou, Wen‐Chang Chang, Tsung‐I Hsu

Advanced Science· Volume 12· Issue 38
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Abstract

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor. Its poor prognosis is primarily due to recurrence and resistance to standard therapies, such as temozolomide (TMZ). Emerging evidence suggests that neuronal excitation within the tumor microenvironment contributes to the progression and chemoresistance of GBM. This study identifies prostaglandin E2 (PGE2) as a key regulator of neuronal activity that promotes tumor resistance. It is demonstrated that PGE2 activates neurons via the prostaglandin E1 (EP1) receptor, leading to intracellular calcium influx and phosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII), which enhances synaptic plasticity. Neuronal excitation results in upregulation of synaptic proteins and neurotransmitter alterations, notably increasing glutamine and asparagine levels, which correlate with heightened chemoresistance. Co‐culture experiments confirmed that PGE2‐stimulated neurons induce resistance in adjacent GBM cells, highlighting a neuron‐tumor interaction that facilitates recurrence. To overcome this resistance mechanism, compound 11 is developed, a novel blood‐brain barrier (BBB)‐permeable celecoxib derivative that effectively inhibits PGE2 signaling. Treatment with compound 11 significantly reduces GBM growth, impairs neuronal excitation, and improves survival outcomes in preclinical models. These findings underscore PGE2‐induced neuronal excitation as a critical driver of drug resistance in GBM, and implicate compound 11 as a promising therapeutic agent to counteract PGE2‐driven tumor recurrence.
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Research context

OpenAlex topics: Cancer, Stress, Anesthesia, and Immune Response · Receptor Mechanisms and Signaling · Inflammatory mediators and NSAID effects

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Research Center for Neuroscience Taipei Medical University Taipei 11031 Taiwan

Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University and National Health Research Institutes Taipei 11031 Taiwan

Taipei Neuroscience Institute Taipei Medical University Taipei 11031 Taiwan

Department of Neurosurgery Shuang Ho Hospital Taipei Medical University Taipei 11031 Taiwan

Chi Mei Medical Center Tainan 71004 Taiwan

School of Pharmacy College of Pharmacy Taipei Medical University Taipei 11031 Taiwan

Institute of Precision Medicine College of Medicine National Sun Yat‐Sen University Kaohsiung 804 Taiwan

National Institute of Cancer Research, National Health Research Institutes Tainan 704 Taiwan

Department of Oncology, National Cheng Kung University Hospital, College of Medicine National Cheng Kung University Tainan 704302 Taiwan

Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine National Cheng Kung University Tainan 704 Taiwan

Department of Pharmacology College of Medicine National Cheng Kung University Tainan 704 Taiwan

TMU Research Center for Drug Discovery Taipei Medical University Taipei 11031 Taiwan

International Master Program in Medical Neuroscience, College of Medical Science and Technology Taipei Medical University Taipei 11031 Taiwan

Department of Molecules‐Signaling‐Development Max‐Planck Institute for Biological Intelligence 82152 Martinsried Germany

Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy Taipei Medical University Taipei 11031 Taiwan

TMU Research Center of Cancer Translational Medicine Taipei 11031 Taiwan

Graduate Institute of Medical Sciences, College of Medicine Taipei Medical University Taipei 11031 Taiwan

Funding

National Science and Technology Council · Taipei Medical University · Chi Mei Medical Center

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