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  3. Modulation of epithelial-mesenchymal transition by gemcitabine: Targeting ionizing radiation-induced cellular senescence in lung cancer cell

Modulation of epithelial-mesenchymal transition by gemcitabine: Targeting ionizing radiation-induced cellular senescence in lung cancer cell

  • Biochem Pharmacol. 2024 Apr 25:224:116234. doi: 10.1016/j.bcp.2024.116234.
Heng Zhou 1,  Chenghao Li 2,  Yanxian Ren 3,  Wen-An Wang 3,  Jiayuan Zhuang 4,  Yue Ren 5,  Lin Shen 5,  Yong Chen 6
Affiliations

Affiliations

  • 1 Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; School of Public Health, Yangzhou University, Yangzhou, China.
  • 2 Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Yangzhou University Medical College, Yangzhou, China. Electronic address: lichenghao22@126.com.
  • 3 School of Public Health, Yangzhou University, Yangzhou, China; The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, China.
  • 4 School of Public Health, Yangzhou University, Yangzhou, China; Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, China.
  • 5 Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Yangzhou University Medical College, Yangzhou, China.
  • 6 Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Yangzhou University Medical College, Yangzhou, China. Electronic address: chenyong_jsyz@sina.com.
PMID: 38670436 DOI: 10.1016/j.bcp.2024.116234
Abstract

Ionizing radiation, a standard therapeutic approach for lung Cancer, often leads to cellular senescence and the induction of epithelial-mesenchymal transition (EMT), posing significant challenges in treatment efficacy and Cancer progression. Overcoming these obstacles is crucial for enhancing therapeutic outcomes in lung Cancer management. This study investigates the effects of ionizing radiation and gemcitabine on lung Cancer cells, with a focus on induced senescence, EMT, and Apoptosis. Human-derived A549, PC-9, and mouse-derived Lewis lung carcinoma cells exposed to 10 Gy X-ray irradiation exhibited senescence, as indicated by morphological changes, β-galactosidase staining, and cell cycle arrest through the p53-p21 pathway. Ionizing radiation also promoted EMT via TGFβ/SMAD signaling, evidenced by increased TGFβ1 levels, altered EMT marker expressions, and enhanced cell migration. Gemcitabine, a first-line lung Cancer treatment, was shown to enhance Apoptosis in senescent cells caused by radiation. It inhibited cell proliferation, induced mitochondrial damage, and triggered caspase-mediated Apoptosis, thus mitigating EMT in vitro. Furthermore, in vivo studies using a lung Cancer mouse model revealed that gemcitabine, combined with radiation, significantly reduced tumor volume and weight, extended survival, and suppressed malignancy indices in irradiated tumors. Collectively, these findings demonstrate that gemcitabine enhances the therapeutic efficacy against radiation-resistant lung Cancer cells, both by inducing Apoptosis in senescent cells and inhibiting EMT, offering potential improvements in lung Cancer treatment strategies.

Keywords

Cellular Senescence; Epithelial-Mesenchymal Transition; Gemcitabine; Ionizing Radiation; Lung Cancer Cell; TGFβ/SMAD.

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