Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by down-regulation of HIF-1α and sphingosine kinase 1.
Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by down-regulation of HIF-1α and sphingosine kinase 1.
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DOI：
10.18632/oncotarget.13115
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发表时间：
2016-12-06
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影响因子：
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通讯作者：
Pchejetski D
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文献类型：
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作者：
Alshaker H;Wang Q;Kawano Y;Arafat T;Böhler T;Winkler M;Cooper C;Pchejetski D
多西他赛耐药是目前前列腺癌治疗中的一个关键问题。鞘氨醇激酶1（SK 1）和磷酸肌醇3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路与前列腺癌化疗耐药性有关。在这里，我们研究了它们的联合靶向是否可以使前列腺癌细胞对多西他赛重新敏感。在对多西他赛不敏感的PC-3和DU 145前列腺癌细胞中，单独使用mTOR抑制剂依维莫司（RAD 001）不会导致显著的细胞死亡，但是，它对低水平（5 nM）的多西他赛强烈致敏。我们发现，mTOR抑制导致缺氧诱导因子-1 α（HIF-1α）蛋白水平和SK 1 mRNA的降低。CoCl 2诱导的HIF-1α蓄积导致了对RAD 001/多西他赛联合治疗的部分耐药性。SK 1过表达完全保护前列腺癌细胞免受RAD 001/多西他赛的影响。通过基因敲除和CoCl 2处理，我们发现SK 1 mRNA的表达位于HIF-1α的下游。在裸鼠的人异种移植物模型中，单一RAD 001和多西他赛疗法分别诱导前列腺肿瘤体积减少23%和15%，而它们的组合导致58%的减少。RAD 001单独或与多西他赛组合抑制了肿瘤内mTOR和SK 1信号传导，然而，如肿瘤大小所证明的，其需要多西他赛才能获得临床疗效。联合治疗耐受性良好，毒性水平与多西他赛单药治疗相似。总体而言，我们的数据表明了多西他赛在前列腺癌中致敏的新机制。这为RAD 001/多西他赛联合治疗前列腺癌的进一步临床应用提供了机制依据。
Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel. In hormone-insensitive PC-3 and DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not lead to significant cell death, however, it strongly sensitized cells to low levels (5 nM) of docetaxel. We show that mTOR inhibition has led to a decrease in hypoxia-inducible factor-1α (HIF-1α) protein levels and SK1 mRNA. HIF-1α accumulation induced by CoCl2 has led to a partial chemoresistance to RAD001/docetaxel combination. SK1 overexpression has completely protected prostate cancer cells from RAD001/docetaxel effects. Using gene knockdown and CoCl2 treatment we showed that SK1 mRNA expression is downstream of HIF-1α. In a human xenograft model in nude mice single RAD001 and docetaxel therapies induced 23% and 15% reduction in prostate tumor volume, respectively, while their combination led to a 58% reduction. RAD001 alone or in combination with docetaxel has suppressed intratumoral mTOR and SK1 signaling, however as evidenced by tumor size, it required docetaxel for clinical efficacy. Combination therapy was well tolerated and had similar levels of toxicity to docetaxel alone. Overall, our data demonstrate a new mechanism of docetaxel sensitization in prostate cancer. This provides a mechanistic basis for further clinical application of RAD001/docetaxel combination in prostate cancer therapy.