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

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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Publication Details

Journal
Cell Death and Disease
Published
2024-08-13
DOI
https://doi.org/10.1038/s41419-024-06985-z
Citations
17
Primary Topic
ATP Synthase and ATPases Research
Type
article
Field-Weighted Citation Impact
3.97

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article

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

Wenli Ma, Minghua Ge, Qian Zeng, Y.-M. Cai et al.
17 citations
Cell Death and Disease
ATP Synthase and ATPases Research
3.97
article

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

Wenli Ma, Minghua Ge, Qian Zeng, Y.-M. Cai, Ru He, Yiqun Hu, Chenhong Qian, Jingyan Ge, Guowan Zheng, Wenzhen Wang, Lingling Ding, Xinxin Ren, Jiajie Xu, Yunye Liu, Tebo Hua, Fahuan Song, Chuanming Zheng, Lei Zhu, Yawen Guo, Haifeng Xu
article en
17 citations

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.

Cell Death and DiseaseVol. 15(8)
Bengbu Medical College (CN), Wenzhou Medical University (CN), First Affiliated Hospital of Wenzhou Medical University (CN), Jiaxing University (CN), Zhejiang Cancer Hospital (CN), Lishui Central Hospital (CN), Ningbo Medical Center Lihuili Hospital (CN), Children's Hospital of Zhejiang University (CN), Zhejiang Provincial People's Hospital (CN), Communication University of Zhejiang (CN), Hangzhou Medical College (CN), Zhejiang University of Technology (CN)
National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 5%
ATP Synthase and ATPases Research
3.97
DOIOpen Access PDFOpenAlex
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