Tryptanthrin targets GSTP1 to induce senescence and increases the susceptibility to apoptosis by senolytics in liver cancer cells

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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Abstract

Targeting senescence has emerged as a promising strategy for liver cancer treatment. However, the lack of a safe agent capable of inducing complete senescence and being combined with senolytics poses a limitation. Here, we screened a natural product library and identified tryptanthrin (TRYP) as a potent inducer of cellular senescence in liver cancer cells both in vitro and in vivo. Mechanistically, Glutathione S-transferase P1 (GSTP1), a key regulator for redox homeostasis, was identified as a target protein for TRYP-induced senescence. TRYP directly bound to GSTP1 and inhibited its enzymatic activity, mediating reactive oxygen species (ROS) accumulation, followed by DNA damage response (DDR), consequently contributing to initiating primary senescence. Furthermore, TRYP triggered DNA damage-dependent activation of NF-κB pathway, which evoked senescence-associated secretory phenotype (SASP), thereby leading to senescence reinforcement. Importantly, TRYP exposed the vulnerability of tumor cells and sensitized senescent cells to apoptosis induced by senolytic agent ABT263, a Bcl2 inhibitor. Taken together, our findings reveal that TRYP induces cellular senescence via GSTP1/ROS/DDR/NF-κB/SASP axis, providing a novel potential application in synergizing with senolytic therapy in liver cancer.

Abstract Image

胰黄素以 GSTP1 为靶标诱导肝癌细胞衰老,并增加肝癌细胞对衰老剂凋亡的敏感性
以衰老为靶点已成为治疗肝癌的一种前景广阔的策略。然而,缺乏一种能够诱导完全衰老并能与衰老剂联合使用的安全药物构成了限制。在这里,我们筛选了一个天然产物库,发现色青素(TRYP)既能诱导肝癌细胞衰老,又能诱导肝癌细胞衰老。从机理上讲,谷胱甘肽 S 转移酶 P1(GSTP1)是氧化还原平衡的关键调节因子,被确定为 TRYP 诱导衰老的靶蛋白。TRYP 直接与 GSTP1 结合并抑制其酶活性,介导活性氧(ROS)积累,继而引起 DNA 损伤反应(DDR),从而导致原发性衰老的发生。此外,TRYP 还触发了 DNA 损伤依赖性的 NF-κB 通路激活,从而诱发衰老相关分泌表型(SASP),进而导致衰老强化。重要的是,TRYP暴露了肿瘤细胞的脆弱性,并使衰老细胞对Bcl2抑制剂ABT263诱导的凋亡敏感。综上所述,我们的研究结果表明,TRYP 可通过 GSTP1/ROS/DDR/NF-κB/SASP 轴诱导细胞衰老,为肝癌中的衰老疗法提供了一种新的潜在协同应用。
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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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