Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells.
Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells.
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DOI：
10.18632/oncotarget.6539
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发表时间：
2016-01-12
期刊：
影响因子：
--
通讯作者：
Ann DK
中科院分区：
文献类型：
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作者：
Chen YR;Tsou B;Hu S;Ma H;Liu X;Yen Y;Ann DK
巨细胞自噬可以促进细胞的存活或死亡，这取决于细胞的背景及其程度。我们假设自噬诱导将与针对自噬货物的治疗剂协同作用。为了验证这一假设，我们用他莫昔芬(TMX)处理乳腺癌MDA-MB-231细胞，TMX通过雌激素受体非依赖的途径诱导自噬。自噬的诱导降低了RRM2的细胞水平，RRM2是核糖核苷酸还原酶(RR)的一个亚单位，RRM2是产生脱氧核糖核苷酸三磷酸(DNTPs)的限速酶。这种自噬诱导剂与我们实验室开发的针对RR的抑制剂COH29通过一种新的机制结合在一起。在体外和体内异种移植模型中，联合治疗对细胞毒性显示出协同作用。这种细胞毒性可通过敲除自噬蛋白ATG5或加入自噬抑制剂氯喹而被阻断。联合治疗还导致dNTP耗尽和大量基因组不稳定，使我们假设结合自噬诱导和RR抑制可以导致快速分裂细胞的有丝分裂灾难。我们认为TMX+COH29联合治疗可能有临床益处。此外，自噬诱导可能是增强化疗药物效果的一般机制。
Macroautophagy can promote cellular survival or death depending on the cellular context and its extent. We hypothesized that autophagy induction would synergize with a therapeutic agent targeting the autophagic cargo. To test this hypothesis, we treated breast cancer MDA-MB-231 cells with tamoxifen (TMX), which induces autophagy through an estrogen receptor-independent pathway. Induction of autophagy reduced cellular levels of RRM2, a subunit of ribonucleotide reductase (RR), the rate limiting enzyme in the production of deoxyribonucleotide triphosphates (dNTPs). This autophagy inducer was combined with COH29, an inhibitor developed in our laboratory that targets RR through a novel mechanism. The combination therapy showed synergistic effects on cytotoxicity in vitro and in an in vivo xenograft model. This cytotoxicity was blocked by knockdown of the autophagy protein ATG5 or addition of chloroquine, an autophagy inhibitor. The combined therapy also induced dNTP depletion and massive genomic instability, leading us to hypothesize that combining autophagy induction with RR inhibition can lead to mitotic catastrophe in rapidly dividing cells. We propose that this TMX + COH29 combined therapy may have clinical benefit. Furthermore, autophagy induction may be a general mechanism for augmenting the effects of chemotherapeutic agents