Glutaminase I isoforms as personalized biomarkers of prostate cancer

摘要 前列腺癌（PCa）是一种异质性疾病。对治疗的反应和预后差异很大 从患者到患者，并且迫切需要可以预测治疗反应和预后的生物标志物。 在试图确定前列腺癌激素治疗的代谢机制时，我们发现， 雄激素受体（AR）在晚期PCa中的一个重要功能是上调 谷氨酰胺酶1（GLS1），其对于癌细胞利用谷氨酰胺以补偿它们的 由于瓦尔堡效应，不能从葡萄糖产生足够的ATP和代谢中间产物。 靶向AR的激素治疗抑制GLS1表达和谷氨酰胺利用，使细胞饥饿死亡。 GLS1有两种亚型，肾型转氨酶（KGA）和转氨酶C（GAC）。我们的工作 表明早期阶段，对前列腺癌敏感的前列腺癌主要表达肾型转氨酶（KGA）， 较弱的AR依赖性GLS1亚型，而晚期的治疗抗性PCa大多表达更多的AR依赖性GLS1亚型。 有效的和AR非依赖性转氨酶C（GAC）。我们已经证明，在GLS 1表达中的这种开关 同种型是重要临床现象的分子基础，包括肿瘤对 激素治疗和最终的治疗抵抗。重要的是，我们还观察到显著的异质性， 在GLS1亚型的表达中。例如，虽然大多数对激素敏感的 癌症表达KGA，少数表达GAC。同样，虽然大多数晚期PCa病例 表达GAC，少数表达KGA。不同植物GLS 1亚型的异源表达 不同疾病阶段PCa的酶活性是有趣的，促使我们确定 它们与PCa患者中观察到的异质性临床结局的可能相关性。我们将研究 GLS 1亚型作为潜在生物标志物的价值，假设主要表达GLS 1的肿瘤 KGA对激素治疗的反应更好，预后更好，而那些主要表达KGA的患者， GAC对激素治疗反应差，预后差。这一假设将得到广泛的检验， 激素敏感性前列腺癌和CRPC的高价值患者肿瘤队列。此外，我们将 测试GLA同种型的差异表达是否与PCa的两种组织学类型相关， AR依赖性腺癌，通常病程较长，而小细胞神经内分泌腺癌 这是AR非依赖性和快速致命的癌症。

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.