The anti-cancer transition-state inhibitor MTDIA inhibits human MTAP, inducing autophagy in humanized yeast.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-30 DOI:10.1242/dmm.052173
Namal V Coorey, Isaac Tollestrup, Peter W Bircham, Jeffrey P Sheridan, Gary B Evans, Vern L Schramm, Paul H Atkinson, Andrew B Munkacsi
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Abstract

Methylthioadenosine-DADMe immucillin-A (MTDIA) is a transition-state analog that potently inhibits the human protein 5'-methylthioadenosine phosphorylase (MTAP) at picomolar concentrations and elicits anti-tumor activity against lung, prostate, colon, cervical, head and neck, and triple-negative breast cancers in cell and animal models. The anti-cancer mechanisms of MTDIA involve elevated methylthioadenosine levels but are not fully understood. The yeast protein MEU1 is functionally equivalent to human MTAP. To gain further understanding, we performed chemical genetic analyses via gene deletion and GFP-tagged protein libraries in yeast that express a member of the human equilibrative nucleoside transporter (ENT) family to permit MTDIA uptake. Genomic and proteomic analyses identified genes and proteins critical to MTDIA bioactivity. Network analysis of these genes and proteins revealed an important link to ribosomal function, which was confirmed by observing reduced levels of ribosomal subunit proteins. Network analysis also implicated autophagy, which was confirmed by analyzing intracellular trafficking of GFP-Atg8 and Phloxine B viability. In yeast, a comparable effect occurred after deletion of MEU1, indicating a single target for MTDIA in yeast. Overall, our yeast model reveals specific components of the ribosome as well as induction of autophagy as integral mechanisms that mediate the bioactivity of MTDIA.

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抗癌甲基硫代腺苷磷酸化酶过渡态抑制剂诱导人源化酵母自噬。
甲基硫代腺苷- dadme免疫蛋白a (MTDIA)是一种过渡态类似物,在皮摩尔浓度下有效抑制5'-甲基硫代腺苷磷酸化酶(MTAP),并在细胞和动物模型中引发抗肺癌、前列腺癌、结肠癌、宫颈癌、头颈癌和三阴性乳腺癌的抗肿瘤活性。MTDIA的抗癌机制涉及甲基硫代腺苷的升高,但尚不完全清楚。MEU1在酵母中表达,其功能与人类的MTAP相当。为了进一步了解,我们在酵母中通过基因缺失和gfp标记的蛋白文库进行了化学遗传分析,以表达人类平衡核苷转运蛋白,以允许MTDIA的摄取。基因组学和蛋白质组学分析确定了MTDIA生物活性的关键基因和蛋白质。这些基因和蛋白质的网络分析揭示了与核糖体功能的重要联系,这与核糖体亚基蛋白的丰度降低证实了这一点。网络分析也与自噬有关,证实了细胞内gfp - at8的运输和苯氧酚B的活力。酵母MEU1的缺失也产生了类似的效果,表明酵母中MTDIA只有一个靶点。总的来说,我们的酵母模型揭示了核糖体的特定成分和自噬诱导是介导MTDIA生物活性的整体机制。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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