2. Academic Validation
  3. ARID3A enhances chemoresistance of pancreatic cancer via inhibiting PTEN-induced ferroptosis

ARID3A enhances chemoresistance of pancreatic cancer via inhibiting PTEN-induced ferroptosis

  • Redox Biol. 2024 May 17:73:103200. doi: 10.1016/j.redox.2024.103200.
Xiaoqi Mao 1,  Jin Xu 1,  Mingming Xiao 1,  Chen Liang 1,  Jie Hua 1,  Jiang Liu 1,  Wei Wang 1,  Xianjun Yu 2,  Qingcai Meng 3,  Si Shi 4
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • 2 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yuxianjun@fudanpci.org.
  • 3 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: mengqingcai@fudanpci.org.
  • 4 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: shisi@fudanpci.org.
PMID: 38781729 DOI: 10.1016/j.redox.2024.103200
Abstract

Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling Sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of Phosphatase and tensin homolog (PTEN), consequently leading to Glutathione Peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated Ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the Ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic Cancer. Notably, both inhibition of ARID3A and enhancement of Ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic Cancer.

Keywords

ARID3A; Chemoresistance; Ferroptosis; Gemcitabine; PTEN; Pancreatic cancer.

Figures
Products