Post-surgical radiotherapy and temozolomide, a chemotherapeutic drug, targeting post-cell division is the current standard of care for glioblastoma (GBM) – the most prevalent and lethal primary tumor of the central nervous system. An aggressive form of brain tumor, GBM is highly resistant to current therapies with high mortality and frequent recurrence. Moreover, GBM cells are highly radioresistant and contribute to tumor progression and recurrence even more aggressively when surviving radiotherapy. Thus, there is an urgent need to revise the standard treatment strategy and develop a new therapy to overcome the radioresistance of GBM cells.
To this end, a team of researchers from Korea and USA led by Professor BuHyun Youn from Pusan National University in Korea has now unveiled a plausible mechanism underlying the radioresistance of GBM cells that involves regulating an internal steady state of lipid within the cells, known as "lipid homeostasis." "Put simply, radioresistant GBM cells prefer to stock up on fatty acids instead of utilizing them as an energy source in order to reduce mitochondrial reactive oxygen species that may cause damage to their DNA, RNA, and proteins, and, in turn, cell death," explains Prof. Youn.
In their study published in Cell Reports Medicine, the researchers derived GBM stem cells from patients and established radioresistant cells for investigation. They showed that diacylglycerol kinase B (DGKB), a regulator of the intracellular level of diacylglycerol (DAG), was significantly suppressed in radioresistant GBM cells. This, in turn, increased DAG accumulation and decreased fatty acid oxidation, reducing mitochondrial lipotoxicity (harmful lipid accumulation in non-adipose tissues) in GBM cells and contributing to their radioresistance. Further, the team showed that the ionizing radiation induced an increase in the level of diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the formation of triglycerides from DAG.
Armed with this understanding, the researchers further demonstrated that the genetic inhibition of DGAT1 suppresses radioresistance. In addition, they discovered that cladribine, a clinical drug, activates DGKB and inhibits DGAT1. This action sensitized GBM cells to radiotherapy both in vitro and in vivo ( in mouse models).
"Our research has revealed cladribine as a radiosensitizer for GBM treatment by drug repurposing, which can offer multiple advantages," says Prof. Youn. "As an FDA-approved oral drug, the side-effects of cladribine are quite manageable and it has been well evaluated for pharmacokinetics. Additionally, the clinical trial period will be considerably shorter than that required for new drug development. In this regard, cladribine could become a standard future treatment for GBM."
Taken together, this study demonstrates that DGKB and DGAT1 are potential therapeutic targets for overcoming GBM radioresistance. Moreover, drugs like cladribine could potentially replace existing treatment options with a new and more effective strategy.
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Reference
DOI: https://doi.org/10.1016/j.xcrm.2022.100880
Authors: Hyunkoo Kang1, Haksoo Lee1, Kyeongmin Kim2, Eunguk Shin1, Byeongsoo Kim1, JiHoon Kang3, Bohkyung Kim4, Jung Sub Lee5, Jae-Myung Lee6, HyeSook Youn7, and BuHyun Youn1,8,
Affiliations:
1Department of Integrated Biological Science, Pusan National University
2Center Research Institute, Samjin Pharm. Co., Ltd.
3Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine
4Department of Food Science and Nutrition, Pusan National University
5Department of Orthopaedic Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine
6Department of Naval Architecture and Ocean Engineering, Pusan National University
7Department of Integrative Bioscience and Biotechnology, Sejong University
8Department of Biological Sciences, Pusan National University
About Pusan National University
Pusan National University, located in Busan, South Korea, was founded in 1946, and is now the no. 1 national university of South Korea in research and educational competency. The multi-campus university also has other smaller campuses in Yangsan, Miryang, and Ami. The university prides itself on the principles of truth, freedom, and service, and has approximately 30,000 students, 1200 professors, and 750 faculty members. The university is composed of 14 colleges (schools) and one independent division, with 103 departments in all.
Website: https://www.pusan.ac.kr/eng/Main.do
About the author
Prof. BuHyun Youn is a Professor of Biological Sciences at Pusan National University in Korea. His group is investigating the mechanism of radioresistance and metabolic reprogramming in GBM. Youn group is also developing therapeutic drugs targeting metabolic rewiring of GBM to improve the efficacy of radiotherapy. Before coming to Pusan National University, he completed Postdoctoral training at ChulHee Kang's lab at Washington State University. In 2004, BuHyun Youn received his Ph.D. in the same lab.
Personal website address: https://biochemistry.pusan.ac.kr
ORCID id: 0000-0002-8010-519X
