Hypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas

Jianxing Yin, Xiefeng Wang, Xin Ge, Fangshu Ding, Zhumei Shi, Zehe Ge, Guang Huang, Ningwei Zhao, Dongyin Chen, Junxia Zhang, Sameer Agnihotri, Yuandong Cao, Jing Ji, Fan Lin, Qianghu Wang, Qigang Zhou, Xiuxing Wang, Yongping You (), Zhimin Lu () and Xu Qian ()
Additional contact information
Jianxing Yin: The First Affiliated Hospital of Nanjing Medical University
Xiefeng Wang: The First Affiliated Hospital of Nanjing Medical University
Xin Ge: Nanjing Medical University
Fangshu Ding: Nanjing Medical University
Zhumei Shi: The First Affiliated Hospital of Nanjing Medical University
Zehe Ge: Nanjing Medical University
Guang Huang: Nanjing Medical University
Ningwei Zhao: China Exposomics Institute
Dongyin Chen: Nanjing Medical University
Junxia Zhang: The First Affiliated Hospital of Nanjing Medical University
Sameer Agnihotri: UPMC Children’s Hospital of Pittsburgh
Yuandong Cao: The First Affiliated Hospital of Nanjing Medical University
Jing Ji: The First Affiliated Hospital of Nanjing Medical University
Fan Lin: Nanjing Medical University
Qianghu Wang: Nanjing Medical University
Qigang Zhou: Nanjing Medical University
Xiuxing Wang: Nanjing Medical University
Yongping You: The First Affiliated Hospital of Nanjing Medical University
Zhimin Lu: Zhejiang University School of Medicine
Xu Qian: The First Affiliated Hospital of Nanjing Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells. This conversion is catalyzed by hypoxanthine phosphoribosyl transferase 1 (HPRT1), which is highly expressed in human GBMs. As the bona fide activator of AMP-activated protein kinase (AMPK), TMZ-derived AICAR activates AMPK to phosphorylate threonine 52 (T52) of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), leading to RNR activation and increased production of dNTPs to fuel the repairment of TMZ-induced-DNA damage. RRM1 T52A expression, genetic interruption of HPRT1-mediated AICAR production, or administration of 6-mercaptopurine (6-MP), a clinically approved inhibitor of HPRT1, blocks TMZ-induced AMPK activation and sensitizes brain tumor cells to TMZ treatment in mice. In addition, HPRT1 expression levels are positively correlated with poor prognosis in GBM patients who received TMZ treatment. These results uncover a critical bifunctional role of TMZ in GBM treatment that leads to chemoresistance. Our findings underscore the potential of combined administration of clinically available 6-MP to overcome TMZ chemoresistance and improve GBM treatment.

Date: 2023
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DOI: 10.1038/s41467-023-41663-2

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