Barfeld Stefan J, Fazli Ladan, Persson Margareta, Marjavaara Lisette, Urbanucci Alfonso, Kaukoniemi Kirsi M, Rennie Paul S, Ceder Yvonne, Chabes Andrei, Visakorpi Tapio, Mills Ian G
Prostate Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
The Vancouver Prostate Centre, University of British Columbia, British Columbia, Canada.
Oncotarget. 2015 May 20;6(14):12587-602. doi: 10.18632/oncotarget.3494.
The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.
雄激素受体是一种关键的转录因子，对前列腺癌（PCa）各个阶段的发展都有影响。此外，其他转录因子也与PCa的不良预后相关，其中c-Myc（MYC）在许多其他癌症中是一种公认的致癌基因。我们之前曾报道，雄激素受体促进糖酵解和合成代谢；许多这些代谢途径在其他癌症中也受MYC调控。在本研究中，我们报告在PCa细胞中，从头嘌呤生物合成以及随后向黄苷酸（XMP）的转化受MYC严格调控，且与雄激素受体活性无关。我们将该途径中的两种酶，磷酸核糖胺甘氨酰胺合成酶（PAICS）和肌苷酸脱氢酶2（IMPDH2）鉴定为组织样本中的PCa生物标志物，并报告已有的抗雄激素药物与临床批准的IMPDH抑制剂霉酚酸（MPA）联合使用时疗效增强。用MPA处理导致细胞三磷酸鸟苷（GTP）水平显著降低，同时伴有核仁应激和p53稳定。总之，靶向嘌呤生物合成提供了一个干扰PCa代谢并增强肿瘤抑制应激反应的机会。
