Fatty acid synthase is a novel therapeutic target in multiple myeloma.
Fatty acid synthase is a novel therapeutic target in multiple myeloma.
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DOI：
10.1111/j.1365-2141.2008.07114.x
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发表时间：
2008-05
影响因子：
6.5
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Okawa Y;Hideshima T;Ikeda H;Raje N;Vallet S;Kiziltepe T;Yasui H;Enatsu S;Pozzi S;Breitkreutz I;Cirstea D;Santo L;Richardson P;Anderson KC
脂肪酸合成酶是治疗多发性骨髓瘤的新靶点。《英国血液学杂志》，141,659-671。上述文章发表在2008年5月7日的在线期刊《Blackwell Synergy》(http://www.blackwell-Synergy.com)上，经作者、杂志主编和Blackwell出版有限公司同意撤回。芬巴尔·科特主编《英国血液学杂志》这项研究探讨了使用小分子抑制剂Cerulenin抑制多发性骨髓瘤(MM)中脂肪酸合成酶(Fas)的生物学意义。蓝菌素在MM细胞系和MM患者细胞中均引起生长抑制，并克服了IL-6、胰岛素样生长因子-1和骨髓基质细胞赋予的生存和生长优势。诱导MM细胞凋亡，对caspase-8、-9、-3和PARP只有适度的激活作用，而且caspase抑制剂Z-VAD-FMK不能抑制蓝精蛋白诱导的细胞凋亡和细胞死亡。此外，蓝精蛋白处理的MM细胞主要上调凋亡诱导因子/核酸内切酶G，这是caspase非依赖性细胞凋亡的介质。重要的是，蓝菌素通过上调GRP78/IRE1JNK/α途径诱导内质网应激反应。C-Jun-NH2末端激酶(JNK)抑制剂SP600215虽然能阻断蓝精蛋白诱导的细胞毒作用，但不能抑制细胞的凋亡和caspase的裂解。此外，蓝菌素与Bortezomib、Melphalan和阿霉素等多种药物具有协同细胞毒作用。因此，我们的结果表明，蓝豆蛋白对Fas的抑制主要触发了MM细胞中caspase非依赖性的细胞凋亡和JNK依赖性的细胞毒作用。本研究证实抑制Fas对MM细胞具有抗肿瘤活性，提示其可能成为MM治疗的新靶点。
Okawa, Y., Hideshima, T., Ikeda, H., Raje, N., Vallet, S., Kiziltepe,T., Yasui, H., Enatsu, S., Pozzi, S., Breitkreutz, I., Cirstea, D., Santo, L.,Richardson, P. & Anderson, K.C. (2008) Fatty acid synthase is a novel therapeutic target in multiple myeloma. British Journal of Haematology, 141, 659–671. The above article, published in the online issue, 141·5 on 7 May 2008 in Blackwell Synergy (http://www.blackwell‐synergy.com), has been retracted by agreement between the authors, the Journal Editor‐in‐Chief and Blackwell Publishing Ltd. Finbarr Cotter Editor‐in‐Chief British Journal of Haematology This study investigated the biological significance of the inhibition of fatty acid synthase (FAS) in multiple myeloma (MM) using the small molecule inhibitor Cerulenin. Cerulenin triggered growth inhibition in both MM cell lines and MM patient cells, and overcame the survival and growth advantages conferred by interleukin‐6, insulin‐like growth factor‐1, and bone marrow stromal cells. It induced apoptosis in MM cell lines with only modest activation of caspase ‐8, ‐9, ‐3 and PARP; moreover, the pan‐caspase inhibitor Z‐VAD‐FMK did not inhibit Cerulenin‐induced apoptosis and cell death. In addition, treatment of MM cells with Cerulenin primarily up‐regulated apoptosis‐inducing factor/endonuclease G, mediators of caspase‐independent apoptosis. Importantly, Cerulenin induced endoplasmic reticulum stress response via up‐regulation of the Grp78/IRE1α/JNK pathway. Although the C‐Jun‐NH2‐terminal kinase (JNK) inhibitor SP600215 blocked Cerulenin‐induced cytotoxicity, it did not inhibit apoptosis and caspase cleavage. Furthermore, Cerulenin showed synergistic cytotoxic effects with various agents including Bortezomib, Melphalan and Doxorubicin. Our results therefore indicate that inhibition of FAS by Cerulenin primarily triggered caspase‐independent apoptosis and JNK‐dependent cytotoxicity in MM cells. This report demonstrated that inhibition of FAS has anti‐tumour activity against MM cells, suggesting that it represents a novel therapeutic target in MM.
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4
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