Glutaminase I isoforms as personalized biomarkers of prostate cancer

摘要 前列腺癌(PCa)是一种异质性疾病。对治疗和预后的反应差异很大 从患者到患者，迫切需要能够预测治疗反应和预后的生物标记物。 在试图确定激素治疗前列腺癌的代谢机制时，我们发现 雄激素受体(AR)在晚期PCa中的一个重要作用是上调 谷氨酰胺酶1(GLS1)对癌细胞利用谷氨酰胺以补偿其 由于华宝效应，不能从葡萄糖中产生足够的三磷酸腺苷和代谢中间产物。 针对AR的激素治疗抑制了GLS1的表达和谷氨酰胺的利用，导致细胞饥饿致死。 GLS1有两种亚型，肾型谷氨酰胺酶(KGA)和谷氨酰胺酶C(GAC)。我们的工作 早期激素敏感型PCa主要表达肾型谷氨酰胺酶(KGA)， AR依赖的GLS1亚型越弱，而晚期耐药的Pca大多表达越多 强效不依赖AR的谷氨酰胺酶C(GAC)。我们已经证明了GLS1表达式中的这个开关 异构体是重要的临床现象的分子基础，包括肿瘤的初始敏感性 激素治疗和最终的治疗抵抗。重要的是，我们还观察到了显著的异质性 在不同情况下的GLS1亚型表达中。例如，虽然大多数荷尔蒙敏感 癌症表达KGA，少数表达GAC。同样，虽然大多数晚期前列腺癌病例 快递GAC，一小部分表达KGA。不同菌株GLS1亚型的异质性表达 不同疾病阶段的PCA酶活性是耐人寻味的，并促使我们确定 它们可能与在PCa患者中观察到的不同临床结果相关。我们会研究 GLS1亚型作为潜在生物标志物的价值 KGA对激素治疗的反应更好，预后更好，而主要表现为 GAC对激素治疗反应差，预后较差。这一假设将在大范围内得到检验， 激素敏感型前列腺癌和慢性前列腺癌的高价值患者肿瘤队列。此外，我们还将 检测GLA异构体的差异表达是否与两种组织学类型的PCa有关， AR依赖的腺癌，与小细胞神经内分泌相比，通常有较长的病程 癌症是一种不依赖AR且迅速致死的疾病。

Abstract Prostate cancer (PCa) is a heterogeneous disease. Responses to therapy and prognosis vary significantly from patient to patient, and biomarkers that can predict therapy response and prognosis are urgently needed. In an attempt to identify metabolic mechanisms of hormonal therapy for PCa, we discovered that an important function of androgen receptor (AR) in advanced PCa is to upregulate the expression of glutaminase 1 (GLS1) which is critical for glutamine utilization by cancer cells to compensate for their inability to produce sufficient ATP and metabolic intermediates from glucose due to the Warburg effect. Hormonal therapy targeting AR inhibits GLS1 expression and glutamine utilization, starving cells to death. GLS1 has two isoforms, kidney-type glutaminase (KGA) and glutaminase C (GAC). Our work demonstrates that early stage, hormone-sensitive PCa mostly expresses kidney-type glutaminase (KGA), the weaker, AR-dependent GLS1 isoform, while late stage, therapy-resistant PCa mostly expresses the more potent and AR-independent glutaminase C (GAC). We have shown that this switch in the expression of GLS1 isoforms is a molecular basis for the important clinical phenomenon including tumors’ initial sensitivity to hormonal therapy and the eventual therapy resistance. Importantly, we also observed significant heterogeneity in the GLS1 isoform expression from case to case. For example, while the majority of hormone sensitive cancers expresses KGA, a minority expresses GAC. Similarly, while most cases of late stage PCa express GAC, a minority expresses KGA. The heterogeneous expression of GLS1 isoforms of different enzymatic activities by PCa of various disease stages was intriguing and prompted us to determine their possible correlations with the heterogeneous clinical outcomes observed in PCa patients. We will study the value of GLS1 isoforms as potential biomarkers with the hypothesis that tumors that predominantly express KGA respond better to hormonal therapy and have better prognosis while those that predominantly express GAC respond poorly to hormonal therapy and have worse prognosis. This hypothesis will be tested in large, highly valuable patient tumor cohorts of hormone sensitive prostate cancer and CRPC. Additionally we will test if differential expression of the GLA isoforms is associated with the two histologic types of PCa, adenocarcinoma that is AR dependent and usually has a protracted disease course vs small cell neuroendocrine carcinoma which is AR-independent and rapidly lethal.