2. Academic Validation
  3. GPI inactivation mediates pentose phosphate pathway flux switch-on inducing temozolomide resistance in glioma stem cell

GPI inactivation mediates pentose phosphate pathway flux switch-on inducing temozolomide resistance in glioma stem cell

  • Cancer Lett. 2026 May 1:645:218384. doi: 10.1016/j.canlet.2026.218384.
Jianxing Yin 1,  Zelei Du 1,  Xingdong Liu 2,  Chenfei Lu 1,  Xiefeng Wang 1,  Yunxiang Chen 1,  Yongping You 1,  Junxia Zhang 3,  Xin Ge 4,  Wei Yan 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, PR China.
  • 2 Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 10070, PR China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 10070, PR China.
  • 3 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, PR China. Electronic address: [email protected].
  • 4 Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 210000, PR China. Electronic address: [email protected].
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, PR China. Electronic address: [email protected].
PMID: 41763452 DOI: 10.1016/j.canlet.2026.218384
Abstract

Temozolomide (TMZ) resistance in glioblastoma (GBM) remains a substantial clinical challenge. Targeting glioma stem cells (GSCs) represents a promising strategy to overcome chemoresistance and tumor recurrence. In this study, we found that GSCs maintain chemoresistance by increasing pentose phosphate pathway (PPP) flux compared with differentiated tumor cells. Following TMZ treatment, the activity of glucose-6-phosphate isomerase (GPI), a key glycolytic enzyme that catalyzes the conversion of glucose-6-phosphate to fructose-6-phosphate, was significantly suppressed in GSCs. Mechanistically, Ataxia Telangiectasia Mutated (ATM), activated by TMZ-induced DNA damage, phosphorylates polo-like kinase 1 (PLK1), promoting its nuclear export. PLK1 subsequently phosphorylates GPI at T215, leading to suppression of GPI activity. Targeting the ATM/PLK1/GPI axis through combinational treatment with rigosertib may therefore represent a therapeutic strategy. Moreover, PLK1 expression and GPI pT215 levels may serve as potential candidate markers for GBM. Collectively, activation of the ATM/PLK1/GPI axis plays a critical role in regulating PPP flux and TMZ resistance in GSCs.

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