The essential role of methylthioadenosine phosphorylase in prostate cancer.
The essential role of methylthioadenosine phosphorylase in prostate cancer.
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DOI：
10.18632/oncotarget.7486
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发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Smiraglia DJ
中科院分区：
文献类型：
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作者：
Bistulfi G;Affronti HC;Foster BA;Karasik E;Gillard B;Morrison C;Mohler J;Phillips JG;Smiraglia DJ
前列腺上皮细胞分泌高水平的乙酰化多胺进入前列腺腔。这种独特的特性增加了连接途径的压力，这些途径被迫增加代谢产物的产生以维持池。甲硫氨酸补救途径将多胺生物合成中损失的一碳单元回收回甲硫氨酸循环，从而允许补充SAM库，从而提供帮助减轻与通过这些途径的高通量相关的代谢应激的机制。参与这一过程的限速酶是甲硫腺苷磷酸化酶（MTAP），虽然在许多癌症中通常缺失，但在前列腺癌中受到保护。我们报告了一组人前列腺癌细胞系以及患者样本中MTAP表达的几乎普遍保留。在代谢扰动后，前列腺癌细胞系上调MTAP，这与SAM水平的恢复相关。此外，在前列腺癌的小鼠模型中，我们发现正常前列腺和患病前列腺都保持比其他组织更高的SAM水平，即使在增加的代谢应激下。最后，我们表明，敲除MTAP，无论是遗传和基因，阻断雄激素敏感的前列腺癌的生长在体内。我们的研究结果强烈表明，甲硫氨酸补救途径是一个主要的球员在前列腺癌的代谢物池的稳态调节，由于他们的高水平的通量通过多胺生物合成途径。因此，该途径，特别是MTAP酶，是前列腺癌的有吸引力的治疗靶点。
Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on the connected pathways, which are forced to increase metabolite production to maintain pools. The methionine salvage pathway recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools providing a mechanism to help mitigate metabolic stress associated with high flux through these pathways. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP), which, although commonly deleted in many cancers, is protected in prostate cancer. We report near universal retention of MTAP expression in a panel of human prostate cancer cell lines as well as patient samples. Upon metabolic perturbation, prostate cancer cell lines upregulate MTAP and this correlates with recovery of SAM levels. Furthermore, in a mouse model of prostate cancer we find that both normal prostate and diseased prostate maintain higher SAM levels than other tissues, even under increased metabolic stress. Finally, we show that knockdown of MTAP, both genetically and pharmacologically, blocks androgen sensitive prostate cancer growth in vivo. Our findings strongly suggest that the methionine salvage pathway is a major player in homeostatic regulation of metabolite pools in prostate cancer due to their high level of flux through the polyamine biosynthetic pathway. Therefore, this pathway, and specifically the MTAP enzyme, is an attractive therapeutic target for prostate cancer.