The Autophagy-Senescence Connection in Chemotherapy: Must Tumor Cells (Self) Eat Before They Sleep?
The Autophagy-Senescence Connection in Chemotherapy: Must Tumor Cells (Self) Eat Before They Sleep?
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DOI：
10.1124/jpet.112.197590
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发表时间：
2012-12-01
影响因子：
3.5
通讯作者：
Gewirtz, David A.
中科院分区：
文献类型：
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作者：
Goehe, Rachel W.;Di, Xu;Gewirtz, David A.
将MCF-7乳腺肿瘤细胞或HCT-116结肠癌细胞暴露于临床相关浓度的阿霉素（阿霉素; Farmitalia Research Laboratories，米兰，意大利）或喜树碱导致自噬和衰老。为了确定自噬是否是化疗诱导衰老所必需的，阿霉素诱导的活性氧产生被N-乙酰半胱氨酸和谷胱甘肽抑制，并且共济失调毛细血管扩张症突变，p53和p21的诱导被神经调节和/或遗传调节。在所有情况下，自噬和衰老都受到抑制。这些实验表明自噬和衰老之间的密切联系反映了它们通过共同的信号传导途径进行的间接调节。通过氯喹和3-甲基腺嘌呤对自噬的药理学抑制以及自噬相关基因ATG 5和ATG 7的基因消融，进一步研究了自噬和衰老之间的潜在关系。然而，通过药理学和遗传学方法抑制自噬不能完全消除衰老反应，这只是减少和/或延迟。总之，我们的研究结果表明，自噬和衰老倾向于平行发生，而且自噬加速了衰老表型的发展。然而，这些反应并不是不可阻挡地联系或相互依赖的，因为当自噬被废除时，衰老就会发生。
Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.