Bianchi-Smiraglia A, Wawrzyniak J A, Bagati A, Marvin E K, Ackroyd J, Moparthy S, Bshara W, Fink E E, Foley C E, Morozevich G E, Berman A E, Shewach D S, Nikiforov M A
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Death Differ. 2015 Nov;22(11):1858-64. doi: 10.1038/cdd.2015.47. Epub 2015 Apr 24.
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 BRAF(V600E) or NRAS(Q61R) 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.
恶性黑色素瘤在人类癌症中具有最高的转移潜能之一。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极大地促进用于黑色素瘤治疗干预的新型药物的设计。在此，我们报告鸟苷单磷酸合酶（GMPS），一种GMP从头生物合成所需的酶，在源自BRAF（V600E）或NRAS（Q61R）人类转移性黑色素瘤的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一个有吸引力的候选者。因此，我们首次证明，由吸水链霉菌产生的GMPS的核苷类似物抑制剂狭霉素A在体外有效抑制黑色素瘤细胞侵袭，并在免疫受损小鼠中抑制致瘤性。我们的数据确定GMPS是黑色素瘤细胞侵袭的强大驱动因素，并保证对狭霉素A作为一种新型抗黑色素瘤药物进行进一步研究。
