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Prosapogenin A induces GSDME-dependent pyroptosis of anaplastic thyroid cancer through vacuolar ATPase
Yunye Liu1, Yawen Guo1,2,3, Qian Zeng4
1Otolaryngology & 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.
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.
Insights
Prosapogenin A (PA) effectively treats anaplastic thyroid cancer (ATC) by triggering cell death via pyroptosis. This compound targets lysosomal acidification, offering a potential new therapy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic thyroid cancer (ATC) is highly aggressive with limited treatment options.
- Prosapogenin A (PA), a compound from traditional Chinese herbs, shows antineoplastic potential.
- The mechanism of PA's action in ATC is not well understood.
Purpose of the Study:
- To investigate the efficacy of Prosapogenin A (PA) against anaplastic thyroid cancer (ATC).
- To elucidate the underlying molecular mechanisms of PA's anti-ATC activity, focusing on pyroptosis and lysosomal function.
Main Methods:
- In vitro and in vivo studies using ATC cell lines and animal models.
- Analysis of pyroptosis markers, including Gasdermin E (GSDME) cleavage.
- Assessment of lysosomal membrane permeabilization (LMP) and lysosomal acidification.
- Investigation of V-ATPase subunit expression (ATP6V1A, ATP6V1B2, ATP6V0C) and function.
Main Results:
- PA demonstrated significant anti-ATC activity in vitro and in vivo.
- PA induced GSDME-dependent pyroptosis in ATC cells.
- PA promoted lysosomal membrane permeabilization (LMP) and lysosomal over-acidification by upregulating V-ATPase subunits.
- Inhibition of lysosomal acidification or V-ATPase subunits attenuated PA's anti-cancer effects.
Conclusions:
- PA exhibits potent anti-ATC effects by inducing lysosomal damage-dependent pyroptosis.
- PA acts as a V-ATPase agonist, targeting lysosomal acidification to trigger cell death.
- PA represents a promising novel therapeutic candidate for anaplastic thyroid cancer treatment.
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