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

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, an

SUBMITTER: Liu Y 

PROVIDER: S-EPMC11322489 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature