PDF(Pubmed)
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.
摘要：
间变性甲状腺癌（ATC）是最具侵袭性和转移性的恶性肿瘤之一，通常由于缺乏有效的治疗而导致致命的结果。原位素A(PA),一种在传统中草药中普遍存在的生物活性化合物，已显示出作为抗肿瘤剂对抗各种人类肿瘤的潜力。然而,其对ATC的影响及潜在机制尚不清楚.这里,我们证明了PA在体外和体内通过诱导GSDME依赖性的ATC细胞焦亡表现出显著的抗ATC活性。机械上,PA促进溶酶体膜透化（LMP），导致激活半胱天冬酶8/3以切割GSDME的组织蛋白酶的释放。值得注意的是,PA显著上调V-ATPase-ATP6V1A的三个关键功能亚基，ATP6V1B2和ATP6V0C-导致溶酶体过度酸化。这种过度酸化加剧了LMP和随后的溶酶体损伤。溶酶体管腔酸化或抑制/敲低这些V-ATPase亚基的中和减弱PA诱导的溶酶体损伤，ATC细胞的焦亡和生长抑制，强调溶酶体酸化和LMP在PA抗癌作用中的关键作用。总之,我们的发现揭示了PA与癌细胞中溶酶体损伤依赖性焦亡之间的新联系.PA可以作为靶向溶酶体酸化的V-ATPase激动剂，为ATC治疗提供了新的潜在治疗选择。
