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Author Notes:

BuHyun Youn, bhyoun72@pusan.ac.kr

Conceptualization, H.Y. and B.Y.; software, H.L.; validation, E.S., Byeongsoo Kim, and J.K.; formal analysis, H.K. and H.L.; investigation, H.K., H.L., K.K., and H.Y.; resources, Bohkyung Kim, J.S.L., J.L., and H.Y.; writing – original draft, H.K. and H.L.; writing – review & editing, B.Y.; supervision, B.Y.; funding acquisition, B.Y.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2020R1A2C2005793) and National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156). We thank Dr. Frederick F. Lang (Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA) for providing GSC11 cells and Hae Yu Kim (Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea) for providing BCL20-HP02 and BCL21-HP03 cells. We also appreciate Sunmi Jo (Department of Radiation Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea) for providing X-ray facilities and ebiogen (Seoul, Republic of Korea) for carrying out RNA sequencing. This manuscript was edited at Life Science Editors.

The authors declare no competing interests.

Subject:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • FATTY-ACID OXIDATION
  • HEPATOMA-CELLS
  • MITOCHONDRIA

DGKB mediates radioresistance by regulating DGAT1-dependent lipotoxicity in glioblastoma

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Journal Title:

CELL REPORTS MEDICINE

Volume:

Volume 4, Number 1

Publisher:

, Pages 100880-100880

Type of Work:

Article | Final Publisher PDF

Abstract:

Glioblastoma (GBM) currently has a dismal prognosis. GBM cells that survive radiotherapy contribute to tumor progression and recurrence with metabolic advantages. Here, we show that diacylglycerol kinase B (DGKB), a regulator of the intracellular concentration of diacylglycerol (DAG), is significantly downregulated in radioresistant GBM cells. The downregulation of DGKB increases DAG accumulation and decreases fatty acid oxidation, contributing to radioresistance by reducing mitochondrial lipotoxicity. Diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the formation of triglycerides from DAG, is increased after ionizing radiation. Genetic inhibition of DGAT1 using short hairpin RNA (shRNA) or microRNA-3918 (miR-3918) mimic suppresses radioresistance. We discover that cladribine, a clinical drug, activates DGKB, inhibits DGAT1, and sensitizes GBM cells to radiotherapy in vitro and in vivo. Together, our study demonstrates that DGKB downregulation and DGAT1 upregulation confer radioresistance by reducing mitochondrial lipotoxicity and suggests DGKB and DGAT1 as therapeutic targets to overcome GBM radioresistance.

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© 2022 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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