Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, Changsha, Hunan 410208, China.
Department of Urology, The First Hospital of Hunan University of Chinese Medicine, China.
Phytomedicine. 2024 Jul;129:155614. doi: 10.1016/j.phymed.2024.155614. Epub 2024 Apr 21.
Cellular senescence is an emerging hallmark of cancers, primarily fuels cancer progression by expressing senescence-associated secretory phenotype (SASP). Caveolin-1 (CAV1) is a key mediator of cell senescence. Previous studies from our group have evidenced that the expression of CAV1 is downregulated by Celastrol (CeT).
To investigate the impact of CeT on cellular senescence and its subsequent influence on post-senescence-driven invasion, migration, and stemness of clear cell renal cell carcinoma (ccRCC).
The expression levels of CAV1, canonical senescence markers, and markers associated with epithelial-mesenchymal transition (EMT) and stemness in clinical samples were assessed through Pearson correlation analysis. Senescent cell models were induced using DOX, and their impact on migration, invasion, and stemness was evaluated. The effects of CeT treatment on senescent cells and their pro-tumorigenic effects were examined. Subsequently, the underlying mechanism of CeT were explored using lentivirus transfection and CRISPR/Cas9 technology to silence CAV1.
In human ccRCC clinical samples, the expression of the canonical senescence markers p53, p21, and p16 are associated with ccRCC progression. Senescent cells facilitated migration, invasion, and enhanced stemness in both ccRCC cells and ccRCC tumor-bearing mice. As expected, CeT treatment reduced senescence markers (p16, p53, p21, SA-β-gal) and SASP factors (IL6, IL8, CXCL12), alleviating cell cycle arrest. However, it did not restore the proliferation of senescent cells. Additionally, CeT suppressed senescence-driven migration, invasion, and stemness. Further investigations into the underlying mechanism demonstrated that CAV1 is a critical mediator of cell senescence and represents a potential target for CeT to attenuate cellular senescence.
This study presents a pioneering investigation into the intricate interplay between cellular senescence and ccRCC progression. We unveil a novel mechanism of CeT to mitigate cellular senescence by downregulating CAV1, thereby inhibiting the migration, invasion and stemness of ccRCC driven by senescent cells. These findings provide valuable insights into the underlying mechanisms of CeT and its potential as a targeted therapeutic approach for alleviating the aggressive phenotypes associated with senescent cells in ccRCC.
细胞衰老作为癌症的新兴标志之一，主要通过表达衰老相关分泌表型（SASP）来促进癌症进展。窖蛋白-1（CAV1）是细胞衰老的关键介质。我们小组的先前研究已经证明，Celastrol（CeT）下调 CAV1 的表达。
研究 CeT 对细胞衰老的影响及其对透明细胞肾细胞癌（ccRCC）衰老后驱动的侵袭、迁移和干性的后续影响。
通过 Pearson 相关性分析评估临床样本中 CAV1、经典衰老标志物以及与上皮-间充质转化（EMT）和干性相关的标志物的表达水平。使用 DOX 诱导衰老细胞模型，并评估其对迁移、侵袭和干性的影响。研究 CeT 处理对衰老细胞及其促肿瘤生成作用的影响。随后，使用慢病毒转染和 CRISPR/Cas9 技术沉默 CAV1 来探索 CeT 的潜在机制。
在人 ccRCC 临床样本中，经典衰老标志物 p53、p21 和 p16 的表达与 ccRCC 进展相关。衰老细胞促进了 ccRCC 细胞和 ccRCC 荷瘤小鼠的迁移、侵袭和增强干性。正如预期的那样，CeT 处理降低了衰老标志物（p16、p53、p21、SA-β-半乳糖苷）和 SASP 因子（IL6、IL8、CXCL12），缓解了细胞周期停滞。然而，它并没有恢复衰老细胞的增殖能力。此外，CeT 抑制了衰老驱动的迁移、侵袭和干性。对潜在机制的进一步研究表明，CAV1 是细胞衰老的关键介质，是 CeT 减轻细胞衰老的潜在靶点。
本研究首次探讨了细胞衰老与 ccRCC 进展之间的复杂相互作用。我们揭示了 CeT 通过下调 CAV1 来减轻细胞衰老的新机制，从而抑制衰老细胞驱动的 ccRCC 的迁移、侵袭和干性。这些发现为 CeT 的潜在机制及其作为减轻 ccRCC 中衰老细胞相关侵袭表型的靶向治疗方法提供了有价值的见解。
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