Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography.
ACS Chem Biol. 2011 Nov 18;6(11):1257-64. doi: 10.1021/cb2002544. Epub 2011 Sep 26.
Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy, but susceptibility to drug resistance limits their efficacy. The marine actinobacterium Salinispora tropica produces salinosporamide A (NPI-0052, marizomib), a potent proteasome inhibitor and promising clinical agent in the treatment of multiple myeloma. Actinobacteria also possess 20S proteasome machinery, raising the question of self-resistance. We identified a redundant proteasome β-subunit, SalI, encoded within the salinosporamide biosynthetic gene cluster and biochemically characterized the SalI proteasome complex. The SalI β-subunit has an altered substrate specificity profile, 30-fold resistance to salinosporamide A, and cross-resistance to the FDA-approved proteasome inhibitor bortezomib. An A49V mutation in SalI correlates to clinical bortezomib resistance from a human proteasome β5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes.
蛋白酶体抑制剂最近已成为癌症化疗的一种治疗策略，但对药物耐药性的易感性限制了它们的疗效。海洋放线菌盐单胞菌产生柳氮磺胺吡啶 A（NPI-0052，马里佐米布），这是一种有效的蛋白酶体抑制剂，也是治疗多发性骨髓瘤的一种有前途的临床药物。放线菌还拥有 20S 蛋白酶体机制，这引发了自身耐药性的问题。我们在柳氮磺胺吡啶生物合成基因簇内鉴定出一种冗余的蛋白酶体β亚基，SalI，并对其进行了生物化学表征。SalI 蛋白酶体复合物的 β 亚基具有改变的底物特异性谱，对柳氮磺胺吡啶 A 的抗性提高了 30 倍，并且对 FDA 批准的蛋白酶体抑制剂硼替佐米具有交叉耐药性。SalI 中的 A49V 突变与人类蛋白酶体β5 亚基 A49T 突变的硼替佐米临床耐药性相关，这表明对天然蛋白酶体抑制剂的固有耐药性可能预测临床结果。
