Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone.
Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone.
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DOI：
10.1186/s40170-015-0137-1
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发表时间：
2015
影响因子：
5.9
通讯作者：
Boothman DA
中科院分区：
文献类型：
--
作者：
Chakrabarti G;Moore ZR;Luo X;Ilcheva M;Ali A;Padanad M;Zhou Y;Xie Y;Burma S;Scaglioni PP;Cantley LC;DeBerardinis RJ;Kimmelman AC;Lyssiotis CA;Boothman DA
胰腺导管腺癌（PDA）激活胞质烟酰胺腺嘌呤二核苷酸磷酸（NADPH）产生的谷氨酰胺依赖性途径，以维持氧化还原稳态并支持增殖。参与该途径的酶（GLS 1（线粒体谷氨酰胺酶1）、GOT 1（细胞质谷氨酸草酰乙酸转氨酶1）和GOT 2（线粒体谷氨酸草酰乙酸转氨酶2））在PDA中高度上调，并且其中，GLS 1的抑制剂最近在临床试验中用于靶向合成代谢谷氨酰胺代谢。然而，这种途径的单一药物抑制是细胞抑制性的，不太可能在控制晚期疾病方面提供持久的益处。在此，我们报告了通过基因或双（双-2-（5-苯基乙酰氨基-1，2，4-噻二唑-2-基）乙基硫醚（BPTES）或CB-839）抑制突变型Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）PDA中的谷氨酰胺代谢来减少NADPH池，使细胞系和肿瘤对拉帕醌（拉帕醌，临床形式ARQ 761）敏感。NAD-Lap是一种NADPH：醌氧化还原酶（NQO 1）-可生物活化的药物，其通过来自药物的无效氧化还原循环的高水平活性氧（ROS）导致NADPH消耗，随后通过聚（ADP核糖）聚合酶（PARP）超活化导致烟酰胺腺嘌呤二核苷酸（NAD）+消耗。NQO 1表达被突变型KRAS信号高度激活。因此，在突变型KRAS、过表达PDA的NQO 1中，与谷氨酰胺代谢抑制同时进行的NQO 1-lap处理导致大量氧化还原失衡、广泛的DNA损伤、快速PARP介导的NAD+消耗和PDA细胞死亡-在NQO 1-低、野生型KRAS表达细胞中未观察到的特征。该治疗策略说明了同时降低谷氨酰胺代谢依赖性肿瘤抗氧化剂防御和诱导超生理ROS形成是杀肿瘤的原理证明，并且该合理设计的组合策略降低了体外和体内两种药剂的所需剂量。GLS 1抑制剂和PDA-lap对PDA肿瘤的非重叠特异性提供了高肿瘤选择性，同时保留了正常组织。本文的在线版本（doi：10.1186/s40170-015-0137-1）包含补充材料，可供授权用户使用。
Pancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway (GLS1 (mitochondrial glutaminase 1), GOT1 (cytoplasmic glutamate oxaloacetate transaminase 1), and GOT2 (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of GLS1 were recently deployed in clinical trials to target anabolic glutamine metabolism. However, single-agent inhibition of this pathway is cytostatic and unlikely to provide durable benefit in controlling advanced disease. Here, we report that reducing NADPH pools by genetically or pharmacologically (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) or CB-839) inhibiting glutamine metabolism in mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) PDA sensitizes cell lines and tumors to ß-lapachone (ß-lap, clinical form ARQ761). ß-Lap is an NADPH:quinone oxidoreductase (NQO1)-bioactivatable drug that leads to NADPH depletion through high levels of reactive oxygen species (ROS) from the futile redox cycling of the drug and subsequently nicotinamide adenine dinucleotide (NAD)+ depletion through poly(ADP ribose) polymerase (PARP) hyperactivation. NQO1 expression is highly activated by mutant KRAS signaling. As such, ß-lap treatment concurrent with inhibition of glutamine metabolism in mutant KRAS, NQO1 overexpressing PDA leads to massive redox imbalance, extensive DNA damage, rapid PARP-mediated NAD+ consumption, and PDA cell death—features not observed in NQO1-low, wild-type KRAS expressing cells. This treatment strategy illustrates proof of principle that simultaneously decreasing glutamine metabolism-dependent tumor anti-oxidant defenses and inducing supra-physiological ROS formation are tumoricidal and that this rationally designed combination strategy lowers the required doses of both agents in vitro and in vivo. The non-overlapping specificities of GLS1 inhibitors and ß-lap for PDA tumors afford high tumor selectivity, while sparing normal tissue. The online version of this article (doi:10.1186/s40170-015-0137-1) contains supplementary material, which is available to authorized users.