Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity
Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity
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DOI：
10.1038/cdd.2015.47
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发表时间：
2015-11-01
影响因子：
12.4
通讯作者：
Nikiforov, M. A.
中科院分区：
文献类型：
--
作者：
Bianchi-Smiraglia, A.;Wawrzyniak, J. A.;Nikiforov, M. A.
恶性黑色素瘤是人类癌症中具有最高转移潜力的肿瘤之一。获得侵袭性表型是黑色素瘤转移的先决条件。阐明黑色素瘤侵袭的分子机制将大大提高黑色素瘤治疗干预新药的设计。在这里，我们报道了鸟苷单磷酸合成酶（GMPS），一种GMP从头生物合成所需的酶，在BRAFV600E或NRASQ61R人类转移性黑色素瘤细胞的侵袭和致瘤性中起主要作用。此外，与原发性黑色素瘤相比，转移性人类黑色素瘤标本中的GMPS水平升高，这表明GMPS是抗黑色素瘤治疗的有吸引力的候选者。因此，我们首次证明了由吸湿链霉菌产生的GMPS核苷类似物抑制剂angstmycin A在体外有效抑制黑色素瘤细胞的侵袭和免疫功能低下小鼠的致瘤性。我们的数据确定GMPS是黑色素瘤细胞侵袭的强大驱动因素，并保证进一步研究古斯霉素a作为一种新的抗黑色素瘤药物。
Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAFV600E or NRASQ61R human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent.