Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer.
Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer.
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DOI：
10.18632/oncotarget.3494
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Mills IG
中科院分区：
文献类型：
--
作者：
Barfeld SJ;Fazli L;Persson M;Marjavaara L;Urbanucci A;Kaukoniemi KM;Rennie PS;Ceder Y;Chabes A;Visakorpi T;Mills IG
雄激素受体是促进前列腺癌（PCa）各个阶段发展的关键转录因子。此外，其他转录因子也与前列腺癌的不良预后有关，其中c-Myc （MYC）是许多其他癌症中公认的癌基因。我们之前报道过AR促进糖酵解和合成代谢；在其他癌症中，许多代谢途径也受myc调控。在这项研究中，我们报道了在PCa细胞中，嘌呤的新生生物合成和随后向XMP的转化受到MYC的严格调控，与AR活性无关。我们在组织样本中鉴定了两种酶PAICS和IMPDH2作为PCa生物标志物，并报告了抗雄激素与临床批准的IMPDH抑制剂霉酚酸（MPA）联合使用的疗效增加。MPA治疗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干扰PCa代谢和增强肿瘤抑制应激反应的机会。
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.
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影响因子：
11.2
作者：
Kasinski AL;Slack FJ
通讯作者：
Slack FJ
影响因子：
2.8
作者：
He, Yujun;Mou, Zhirong;Wu, Yuzhang
通讯作者：
Wu, Yuzhang
影响因子：
4.8
作者：
Hawksworth, D.;Ravindranath, L.;Petrovics, G.
通讯作者：
Petrovics, G.
影响因子：
11.2
作者：
Huang, Min;Itahana, Koji;Mitchell, Beverly S.
通讯作者：
Mitchell, Beverly S.
SAICAR刺激丙酮酸激酶同工型M2，并在葡萄糖有限的条件下促进癌细胞的存活。
DOI：
10.1126/science.1224409
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Keller KE;Tan IS;Lee YS
通讯作者：
Lee YS