MOE Key Laboratory of Laser Life Science & College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Department of Pain Management, The First Affiliated Hospital, Jinan University, Guangzhou, 5610632, China.
Apoptosis. 2019 Oct;24(9-10):758-772. doi: 10.1007/s10495-019-01555-7.
In contrast to the well-known anti-tumor mechanisms of aspirin in inducing apoptosis or autophagy, we here for the first time report oncosis induced by aspirin in tumor cells. In vitro and in vivo analysis showed that aspirin induced compromised Bcl-XL level and subsequent ATP depletion. Overexpression of CFP-Bcl-XL in Hela and A549 cells observably inhibited aspirin-induced ATP depletion and almost completely inhibited the aspirin-induced cells bubbling, while pharmacological inhibition of endogenous Bcl-XL activity by ABT-737 remarkably promoted aspirin-induced ATP depletion and cells bubbling, suggesting the key inhibitory role of Bcl-XL in aspirin-induced oncosis. Overexpression of Bax/Bad significantly promoted aspirin-induced oncosis. In addition, cells cultured in a glucose-free medium with low ATP level exhibited higher percentage of bubbling cells than the cells cultured in a glucose medium with high ATP level under aspirin treatment, indicating the important role of ATP depletion in aspirin-induced oncosis. Furthermore, caspase-3 was demonstrated to be not involved in aspirin-induced oncosis. Animal studies showed that aspirin treatment significantly inhibited tumors growth, but did not induce toxicities to mice. Collectively, aspirin inhibits tumors growth in mice and induces oncosis in which the compromised Bcl-XL and intracellular ATP depletion play a dominant role, which provides insights into the therapeutic strategy of aspirin in oncology.
与阿司匹林诱导细胞凋亡或自噬等众所周知的抗肿瘤机制相反，我们首次报道了阿司匹林在肿瘤细胞中诱导胀亡的现象。体外和体内分析表明，阿司匹林诱导 Bcl-XL 水平降低，随后导致 ATP 耗竭。在 Hela 和 A549 细胞中转染 CFP-Bcl-XL 可明显抑制阿司匹林诱导的 ATP 耗竭，并几乎完全抑制阿司匹林诱导的细胞冒泡，而通过 ABT-737 抑制内源性 Bcl-XL 活性可显著促进阿司匹林诱导的 ATP 耗竭和细胞冒泡，表明 Bcl-XL 在阿司匹林诱导的胀亡中起关键抑制作用。 Bax/Bad 的过表达显著促进了阿司匹林诱导的胀亡。此外，在阿司匹林处理下，在缺乏葡萄糖和低 ATP 水平的培养基中培养的细胞比在富含葡萄糖和高 ATP 水平的培养基中培养的细胞表现出更高比例的冒泡细胞，表明 ATP 耗竭在阿司匹林诱导的胀亡中起重要作用。此外，caspase-3 不参与阿司匹林诱导的胀亡。动物研究表明，阿司匹林治疗显著抑制肿瘤生长，但不会引起小鼠毒性。总之，阿司匹林在小鼠中抑制肿瘤生长，并诱导胀亡，其中 Bcl-XL 水平降低和细胞内 ATP 耗竭起主导作用，这为阿司匹林在肿瘤学中的治疗策略提供了新的思路。
