Dr. Qian and his group reveals the role of mitochondrial biosynthesis inhibition by PGC-1α degradation in glioma radiotherapy resistance.
On April 4, 2023, Cancer Research published the latest work from Prof. Xu Qian’s lab as a cover article titled "PGC-1α degradation suppresses mitochondrial biogenesis to confer radiation resistance in glioma". This study reveals radiotherapy induces phosphorylation and subsequent ubiquitination-induced degradation of PGC-1α protein in glioma cells, which in turn suppresses mitochondrial biogenesis and reactive oxygen species (ROS) production, thus revealing the mechanism of self-protective radiotherapy resistance in glioma cells.
Glioma is the most prevalent primary tumor of the central nervous system in adults. Glioblastomas (GBM), a grade IV glioma, represent the most malignant intrinsic brain tumor. Despite the growing focus on targeted therapies for GBM treatment, radiotherapy remains a clinically effective approach. However, radiotherapy only provides palliative relief due to the inevitable development of radioresistance. This emphasizes the necessity to elucidate mechanisms underlying radioresistance and develop novel strategies to overcome them in order to improve the unfavorable prognosis.
This study presents integrated transcriptomic analyses of glioma specimens and cell lines, revealing the suppression of mitochondrial metabolic pathways in radioresistant gliomas. The downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α), a pivotal regulator governing mitochondrial biogenesis and metabolism, is associated with glioma recurrence, poor prognosis, and reduced response to radiotherapy in patients with glioma. Furthermore, the subpopulation of low-mitochondrial-mass glioma cells exhibits diminished PGC1α expression and heightened resistance to radiotherapy treatment.
Mechanistically, this study revealed that DNA-dependent protein kinase phosphorylated PGC1α at serine (S) 636 in response to irradiation. Subsequently, phosphorylation at S636 facilitated the binding of PGC1α to the E3 ligase RNF34, promoting its degradation. The restoration of PGC1α activity through expression of the PGC1α S636A mutation or coadministration of a small-molecule PGC1α activator ZLN005 enhanced radiosensitivity in resistant glioma cells by reactivating mitochondria-related reactive oxygen species production and inducing apoptotic effects both in vitro and in vivo.
Postgraduate students Mengjie Zhao and Yanhui Li from the School of Public Health of Nanjing Medical University, along with postgraduate student Chenfei Lu from the First Affiliated Hospital of Nanjing Medical University, are the co-first authors of this paper. Prof. Xu Qian from the School of Public Health of Nanjing Medical University, Prof. Zhumei Shi from the First Affiliated Hospital of Nanjing Medical University, and Prof Kun Yang from the Brain Hospital of Nanjing Medical University are the co-corresponding authors. We would like to express our gratitude to Prof. Wentao Liu and his team at the School of Basic Medical Sciences for their assistance in designing and creating the cover images for this study.
Link to original article: https://doi.org/10.1158/0008-5472.CAN-22-3083
