Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase
Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase
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DOI：
10.1074/jbc.m110.198374
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Schramm, Vern L.
中科院分区：
文献类型：
--
作者：
Basu, Indranil;Locker, Joseph;Schramm, Vern L.
s -腺苷蛋氨酸（AdoMet）挽救酶5'-甲基硫腺苷磷酸化酶（MTAP）已被认为是癌症靶点和肿瘤抑制因子。我们在人类肺癌的小鼠异种移植中验证了这些假设。甲基硫代- dadme - immucillin - a（一种口服、无毒、皮摩尔过渡态类似物）抑制MTAP，阻断了5'-甲基硫代腺苷（MTA）的AdoMet回收。MTDIA治疗后，血液、尿液和肿瘤中MTA水平升高。MTDIA治疗抑制了免疫缺陷Rag2(-/-) γ C-/-和NCr-nu小鼠的A549（人非小细胞肺癌）和H358（人细支气管肺泡非小细胞肺癌细胞）异种移植瘤的生长。由于MTDIA对体内治疗A549 MTAP（-/-）和H358 MTAP（+/+）肿瘤有效，因此系统性MTA积累与肿瘤抑制代谢物有关。治疗小鼠的肿瘤显示MTA增加，多胺减少，但AdoMet、蛋氨酸或腺嘌呤水平变化不大。治疗和未治疗小鼠A549肿瘤的基因表达谱显示，62个mrna上调，63个mrna下调（>= 3倍）。MTDIA在异种移植物中的抗肿瘤活性支持MTAP作为肺癌治疗的靶点。
The S-adenosylmethionine (AdoMet) salvage enzyme 5'-methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a tumor suppressor. We tested these hypotheses in mouse xenografts of human lung cancers. AdoMet recycling from 5'-methylthioadenosine (MTA) was blocked by inhibition of MTAP with methylthio-DADMe-Immucillin-A (MTDIA), an orally available, nontoxic, picomolar transition state analogue. Blood, urine, and tumor levels of MTA increased in response to MTDIA treatment. MTDIA treatment inhibited A549 (human non-small cell lung carcinoma) and H358 (human bronchioloalveolar non-small cell lung carcinoma cells) xenograft tumor growth in immunodeficient Rag2(-/-) gamma C-/- and NCr-nu mice. Systemic MTA accumulation is implicated as the tumor-suppressive metabolite because MTDIA is effective for in vivo treatment of A549 MTAP(-/-) and H358 MTAP(+/+)umors. Tumors from treated mice showed increased MTA and decreased polyamines but little alteration in AdoMet, methionine, or adenine levels. Gene expression profiles of A549 tumors from treated and untreated mice revealed only modest alterations with 62 up-regulated and 63 down-regulated mRNAs (>= 3-fold). MTDIA antitumor activity in xenografts supports MTAP as a target for lung cancer therapy.