GLS1两种剪接体（KGA和GAC）的转换对激素非依赖型前列腺癌进展的影响的机制研究

Prostate cancer (PCa) is one of the most commonly diagnosed malignancy in men. For patients with advanced or metastatic PCa where local therapies can no longer be applied, the treatment of choice is androgen deprivation therapy (ADT) which inhibits androgen production and/or blocks androgen receptor (AR) function. However, this therapy is not curative and cancer recurs after an initial response period averaging 18 months. This recurrent tumor is known as castration-resistant prostate cancer (CPRC). To treat CRPC, newer agents such as enzalutamide and abiraterone, which better block AR signaling and/or inhibit intratumoral androgen synthesis, have been used in clinic. However, the therapeutic effects using these AR-targeting agents are generally short-lived, and resistance to therapy develops quickly and finally PCa becomes to be androgen-independent (AIPC).. Unfortunately, there is currently no effective therapy for AIPC, and thus development of new therapeutic strategies for these PCa patients is urgently needed. Of interest, accumulating evidences have demonstrated the critical role of glutamine metabolism in supporting cancer cell survival and proliferation. Our preliminary data also showed that compared to androgen-dependent PCa (ADPC), AIPC was much more addicted to glutamine. We further observed that the two splicing variants (KGA and GAC) of glutaminase 1 (GLS1), the rate-limited enzyme of glutaminolysis, express differentially in cancer cells of ADPC and AIPC. Specifically speaking, GAC is the dominant isoform of GLS1 in AIPC while KGA shows a stronger pattern in ADPC. According to these findings , we hypothesize that while the KGA expression is controlled by AR function in ADPC cells, targeting AR therapy results in switch of the expression GLS1 splicing variants from KGA to GAC, allowing PCa cells to effectively catalyze glutamine and provide energy that is required for AR-independent cell growth. In this study, we will thus investigate the detailed mechanisms of how the switch of KGA expression to GAC expression occurs during progression of PCa, and determine whether targeting GAC can be a potential therpeutic strategy for clinical management of AIPC.

传统的去势治疗（ADT）通过抑制雄激素受体（AR）的活性治疗激素依赖型前列腺癌（ADPC），但也伴随去势抵抗，由ADPC进展为激素非依赖型前列腺癌（AIPC），成为临床治疗难点。课题组前期研究表明：1)AIPC更加依赖谷氨酰胺；2)谷氨酰胺代谢途径中的限速酶GLS1具有两种剪接体（KGA和GAC），且在不同阶段的前列腺癌组织中存在差异性表达（ADPC高表达KGA而AIPC高表达GAC）。我们推测：KGA向GAC的转换过程是ADPC进展为AIPC的潜在机制，即KGA受AR调控，ADT抑制其表达，由此增强ADT疗效；而非AR调控的GAC逐渐成为GLS1的主要形式，保证肿瘤细胞利用谷氨酰胺维持存活，逃避ADT，促使疾病发展为AIPC。本课题拟通过探究AR如何差异性调控KGA和GAC的表达，阐明两种剪接体的转换对AIPC的发生所具有的影响；并明确GAC对ADT的抵抗作用，寻找AIPC治疗的新靶点。

前列腺癌是常见的泌尿生殖系统恶性肿瘤，在西方男性中高发，近年来在我国男性，尤其是老年男性人群中的发病比例亦呈逐年攀高的趋势。由于其属于雄激素依赖型肿瘤，因此，除去手术及放疗根治外，降低乃至剥夺机体内雄激素水平对于治疗晚期前列腺肿瘤的患者同样可以收获一定的临床治疗效果。但最终所有患者会产生治疗抵抗，进展为去势抵抗型前列腺癌，从而面临无特效治疗手段的窘境。去势抵抗型前列腺癌的发病机制以及治疗一直是临床及基础研究的热门话题。本课题发现晚期前列腺癌虽然不再依赖雄激素，但肿瘤细胞表现出对谷氨酰胺极高的依赖性，并且，谷氨酰胺代谢途径中的限速酶谷氨酰胺酶1（GLS1）存在两种功能不同的剪接体（KGA和GAC），其在不同时期的前列腺癌组织中（早期雄激素依赖和晚期雄激素非依赖）存在差异性表达。并且这两种剪接体在前列腺癌由激素依赖进展为激素非依赖的过程中发生了转换。这种剪接体的转换受雄激素受体（AR）信号转导通路影响，极有可能是介导前列腺癌产生去势抵抗并进展为去势抵抗型前列腺癌的重要机制。具体来说，GLS1是受AR调控的基因，并且AR介导了G LS1的剪接过程，即在AR存在或AR活化的状态下，GLS1倾向于剪接为KGA；而在AR缺失或AR失活的状态下，GLS1更多地以GAC的形式出现。这也解释了晚期前列腺癌（大部分为AR变异或AR缺失）中大量表达GAC、增强肿瘤细胞对谷氨酰胺利用的现象。..CB-839是GLS1的选择性抑制剂，并且在同为激素相关的乳腺癌中被证实对高表达GAC的肿瘤类型有着独特的肿瘤抑制优势。本课题通过体内、体外模型，详细阐明了CB-839对于晚期前列腺癌的抑制效应，并且这种抑制效应在高表达KGA的激素依赖型前列腺癌模型中收效甚微。因此，通过应用CB-839抑制GAC的活性，阻断肿瘤细胞对谷氨酰胺的利用，可成为治疗晚期前列腺癌的新的治疗策略。课题组希望通过相关研究，设计出针对谷氨酰胺代谢途径中关键酶的特异性抑制剂，以期为晚期前列腺癌患者提供更多的治疗选择。

内容获取失败，请点击重试