2. Academic Validation
  3. Prosapogenin A induces GSDME-dependent pyroptosis of anaplastic thyroid cancer through vacuolar ATPase activation-mediated lysosomal over-acidification

Prosapogenin A induces GSDME-dependent pyroptosis of anaplastic thyroid cancer through vacuolar ATPase activation-mediated lysosomal over-acidification

  • Cell Death Dis. 2024 Aug 13;15(8):586. doi: 10.1038/s41419-024-06985-z.
Yunye Liu # 1,  Yawen Guo # 1 2 3,  Qian Zeng 4,  Yiqun Hu 1 2 3,  Ru He 1,  Wenli Ma 5,  Chenhong Qian 6,  Tebo Hua 7,  Fahuan Song 1 2 3,  Yefeng Cai 8,  Lei Zhu 9,  Xinxin Ren 1 2 3,  Jiajie Xu 1 2 3,  Chuanming Zheng 1 2 3,  Lingling Ding 1,  Jingyan Ge 4,  Wenzhen Wang 4,  Haifeng Xu 10,  Minghua Ge 11 12 13,  Guowan Zheng 14 15 16
Affiliations

Affiliations

  • 1 Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China.
  • 3 Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, Zhejiang, China.
  • 4 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
  • 5 Bengbu Medical College, Bengbu, Anhui, China.
  • 6 The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
  • 7 Department of Thyroid Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China.
  • 8 Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 9 Department of Thyroid Surgery, The Fifth Hospital Affiliated to Wenzhou Medical University, Lishui Central Hospital, Lishui City, Zhejiang Province, China.
  • 10 Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
  • 11 Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China. geminghua@hmc.edu.cn.
  • 12 Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China. geminghua@hmc.edu.cn.
  • 13 Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, Zhejiang, China. geminghua@hmc.edu.cn.
  • 14 Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China. guowan.zheng@ki.se.
  • 15 Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China. guowan.zheng@ki.se.
  • 16 Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, Zhejiang, China. guowan.zheng@ki.se.
  • # Contributed equally.
PMID: 39138191 DOI: 10.1038/s41419-024-06985-z
Abstract

Anaplastic thyroid Cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent Pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate Caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase-ATP6V1A, ATP6V1B2, and ATP6V0C-resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, Pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA's Anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent Pyroptosis in Cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.

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