Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis.
Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis.
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DOI：
10.1158/0008-5472.can-08-3157
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发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Kung, Hsing Jien
中科院分区：
文献类型：
--
作者：
Kim, Randie H.;Coates, Jodi M.;Bowles, Tawnya L.;McNerney, Gregory P.;Sutcliffe, Julie;Jung, Jae U.;Gandour-Edwards, Regina;Chuang, Frank Y. S.;Bold, Richard J.;Kung, Hsing Jien
精氨酸剥夺作为抗癌疗法在历史上取得了有限的成功。聚乙二醇化精氨酸脱亚胺酶（ADI-PEG 20）的发展重新引起了人们对精氨酸剥夺治疗某些癌症的兴趣。ADI-PEG 20的功效与乙酰氨基琥珀酸合成酶（ASS）缺乏直接相关。CWR 22 Rv 1前列腺癌细胞不表达ASS（精氨酸合成中的限速酶），并且在体外对ADI-PEG 20敏感。有趣的是，0.3 μg/mL ADI-PEG 20引起的细胞凋亡发生在处理后96小时，并且不依赖于半胱天冬酶。ADI-PEG 20在体内的作用表明，microPET可降低肿瘤活性，并且作为单药治疗以及与多西他赛联合治疗CWR 22 Rv 1小鼠异种移植物可降低肿瘤生长。此外，我们证明了自噬是由ADI-PEG 20引起的单个氨基酸消耗诱导的。在这里，自噬是在0.3 μg/mL ADI-PEG 20处理的1至4小时内检测到的早期事件，并且是CWR 22 Rv 1细胞中对ADI-PEG 20的初始保护性反应。值得注意的是，氯喹和Beclin 1 siRNA敲低对自噬的抑制增强并加速了ADI-PEG 20诱导的细胞死亡。表达减少的ASS的PC 3细胞也经历自噬，并且对自噬抑制和ADI-PEG 20处理有响应。相反，LNCaP细胞高度表达ASS，因此对ADI-PEG 20和自噬抑制都有抗性。这些数据表明ASS缺陷、自噬和ADI-PEG 20导致的细胞死亡之间存在相互关系。最后，88个前列腺肿瘤样本的组织微阵列缺乏ASS表达，表明ADI-PEG 20是治疗前列腺癌的潜在新疗法。
Arginine deprivation as an anti-cancer therapy has historically been met with limited success. The development of pegylated arginine deiminase (ADI-PEG20) has renewed interest in arginine deprivation for the treatment of some cancers. The efficacy of ADI-PEG20 is directly correlated with argininosuccinate synthetase (ASS) deficiency. CWR22Rv1 prostate cancer cells do not express ASS, the rate-limiting enzyme in arginine synthesis, and are susceptible to ADI-PEG20 in vitro. Interestingly, apoptosis by 0.3 μg/mL ADI-PEG20 occurs 96 hours post treatment and is caspase-independent. The effect of ADI-PEG20 in vivo reveals reduced tumor activity by microPET as well as reduced tumor growth as a monotherapy and in combination with docetaxel against CWR22Rv1 mouse xenografts. In addition, we demonstrate autophagy is induced by single amino acid depletion by ADI-PEG20. Here, autophagy is an early event that is detected within 1 to 4 hours of 0.3 μg/mL ADI-PEG20 treatment and is an initial protective response to ADI-PEG20 in CWR22Rv1 cells. Significantly, the inhibition of autophagy by chloroquine and Beclin1 siRNA knockdown enhances and accelerates ADI-PEG20-induced cell death. PC3 cells, which express reduced ASS, also undergo autophagy and are responsive to autophagy inhibition and ADI-PEG20 treatment. In contrast, LNCaP cells highly express ASS and are therefore resistant to both ADI-PEG20 and autophagic inhibition. These data point to an interrelationship among ASS deficiency, autophagy, and cell death by ADI-PEG20. Finally, a tissue microarray of 88 prostate tumor samples lacked expression of ASS, indicating ADI-PEG20 is a potential novel therapy for the treatment of prostate cancer.