Ambrosini Grazia, Seelman Sharon L, Schwartz Gary K
Department of Medicine, Laboratory of New Drug Development, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 2009 Aug 1;69(15):6115-21. doi: 10.1158/0008-5472.CAN-08-3024. Epub 2009 Jul 21.
Drg1 was identified as a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. Its expression is associated with resistance to irinotecan (CPT-11) therapy in preclinical colorectal cancer models both in vitro and in vivo. However, the functional significance of Drg1 in these processes is unknown. We have shown for the first time that Drg1 directly binds to the BH3-only proapoptotic protein Bim. Depletion of Drg1 by small interfering RNA induced up-regulation of Bim and its accumulation in the mitochondria, which correlated with loss of mitochondrial membrane potential and induction of apoptosis in cells exposed to SN-38. Further analyses revealed that Drg1 promotes degradation of Bim through the Cullin2/ElonginB-CIS ubiquitin-protein ligase complex. Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation.
Drg1被鉴定为人类结肠癌和前列腺癌中与分化相关的假定转移抑制基因。在临床前结直肠癌模型中，其表达与体外和体内对伊立替康（CPT-11）治疗的抗性相关。然而，Drg1在这些过程中的功能意义尚不清楚。我们首次表明，Drg1直接与仅含BH3结构域的促凋亡蛋白Bim结合。通过小干扰RNA耗尽Drg1会诱导Bim上调及其在线粒体中的积累，这与线粒体膜电位丧失以及暴露于SN-38的细胞中凋亡的诱导相关。进一步分析表明，Drg1通过Cullin2/ElonginB-CIS泛素-蛋白连接酶复合物促进Bim的降解。相反，在没有Drg1的情况下，Bim被稳定化并更大量地与Hsp70结合。这些结果表明，Drg1通过增强蛋白酶体介导的Bim降解使癌细胞对化疗更具抗性。
