STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious.
STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious.
复制标题
STAT3 介导的自噬依赖性可识别自噬抑制可能有效的乳腺癌亚型。
DOI：
10.1158/0008-5472.can-13-3470
复制
发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Thorburn A
中科院分区：
文献类型：
--
作者：
Maycotte P;Gearheart CM;Barnard R;Aryal S;Mulcahy Levy JM;Fosmire SP;Hansen RJ;Morgan MJ;Porter CC;Gustafson DL;Thorburn A
自噬是一种蛋白质和细胞器降解途径，参与包括癌症在内的多种疾病。最近的证据表明，自噬是肿瘤细胞中的一种细胞存活机制，并且其抑制，特别是与其他治疗相结合可能是有益的，但尚不清楚当自噬被抑制时，是否所有癌细胞的行为都是相同的。我们在一组乳腺癌细胞系中抑制了自噬，发现其中一些细胞系即使在营养丰富的条件下也依赖自噬生存，而其他细胞系只有在受到压力时才需要自噬。在非应激条件下的存活是由于STAT3活性的细胞类型特异性自噬调节，并且这种表型在三阴性细胞系中富集。这种自噬依赖性影响对治疗的反应，因为自噬抑制在体内减少了自噬依赖性乳腺肿瘤的肿瘤生长，而在自噬非依赖性乳腺肿瘤中则没有，而自噬抑制剂和其他药物的联合治疗在自噬依赖性细胞中优先具有协同作用。这些结果意味着自噬依赖性代表了肿瘤细胞的特异性特征，其中自噬抑制将更有效。此外，我们的研究结果表明，自噬抑制可能是目前缺乏有效靶向治疗的三阴性乳腺癌的潜在治疗策略。
Autophagy is a protein and organelle degradation pathway that is involved in diverse diseases including cancer. Recent evidence suggests that autophagy is a cell survival mechanism in tumor cells and that its inhibition especially in combination with other therapy could be beneficial but it remains unclear if all cancer cells behave the same way when autophagy is inhibited. We inhibited autophagy in a panel of breast cancer cell lines and found that some of them are dependent on autophagy for survival even in nutrient rich conditions without any additional stress while others need autophagy only when stressed. Survival under unstressed conditions is due to cell type specific autophagy regulation of STAT3 activity and this phenotype is enriched in triple negative cell lines. This autophagy-dependency affects response to therapy because autophagy inhibition reduced tumor growth in vivo in autophagy-dependent but not in autophagy-independent breast tumors while combination treatment with autophagy inhibitors and other agent was preferentially synergistic in autophagy-dependent cells. These results imply that autophagy-dependence represents a tumor cell specific characteristic where autophagy inhibition will be more effective. Moreover, our results suggest that autophagy inhibition might be a potential therapeutic strategy for triple negative breast cancers, which currently lack an effective targeted treatment.