2. Academic Validation
  3. Pentose phosphate recycling driven by Gli1 contributes to chemotherapy resistance in cancer cells

Pentose phosphate recycling driven by Gli1 contributes to chemotherapy resistance in cancer cells

  • Cancer Lett. 2025 May 28:618:217633. doi: 10.1016/j.canlet.2025.217633.
Qiangsheng Hu 1,  Cong Jiang 2,  Yi Qin 3,  Borui Li 3,  Jingyi Wang 4,  Ting Wang 3,  Shunrong Ji 3,  Zeng Ye 3,  Qing Dang 3,  Mingyang Liu 5,  Xianjun Yu 6,  Xiaowu Xu 7
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
  • 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
  • 3 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • 4 Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, QLD, 4067, Saint Lucia.
  • 5 State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: liumy@cicams.ac.cn.
  • 6 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yuxianjun@fudanpci.org.
  • 7 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: xuxiaowu@fudanpci.org.
PMID: 40090571 DOI: 10.1016/j.canlet.2025.217633
Abstract

The Hedgehog Signaling Pathway plays an important role in Cancer development and chemotherapy resistance. However, whether the pathway functions depend on the metabolic reprogramming of Cancer cells has not been well studied. In this study, we found that the expression level of Gli1, a key transcription factor downstream of the Hedgehog Signaling Pathway, is significantly increased in patients with pancreatic Cancer resistant to gemcitabine neoadjuvant chemotherapy. Through metabolomics analysis, we confirmed that Gli1 can promote the transformation of Cancer cells from a glycolytic-dominated metabolic pattern to a unique metabolic pattern called "Pentose Phosphate Recycling". Transcriptome Sequencing and in vitro experiments suggest that Gli1 promotes pentose phosphate recycling through transcriptional activation of key Enzymes Phosphogluconate dehydrogenase (PGD) and Transketolase (TKT). The identified metabolic rerouting in oxidative and non-oxidative pentose phosphate pathway has important physiological roles in maximizing NADPH reduction and nucleotide synthesis. Therefore, the pentose phosphate cycle driven by Gli1 can resist gemcitabine-induced DNA damage by promoting pyrimidine synthesis and resist gemcitabine-induced Ferroptosis by scavenging lipid Reactive Oxygen Species (Lipid ROS). Combining the Gli1 inhibitor GANT21 with gemcitabine exerts a maximal tumor suppressor effect by simultaneously promoting DNA damage and Ferroptosis. Collectively, these results reveal that Gli1 drives chemotherapy resistance in Cancer cells by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for reversing chemotherapy resistance.

Keywords

Ferroptosis; Gemcitabine resistance; Hedgehog/GLI signaling pathway; Pancreatic ductal adenocarcinoma; Pentose phosphates recycling.

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