Inhibition of NF-κB Signaling by Quinacrine Is Cytotoxic to Human Colon Carcinoma Cell Lines and Is Synergistic in Combination with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) or Oxaliplatin
Inhibition of NF-κB Signaling by Quinacrine Is Cytotoxic to Human Colon Carcinoma Cell Lines and Is Synergistic in Combination with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) or Oxaliplatin
复制标题
DOI：
10.1074/jbc.m109.091645
复制
发表时间：
2010-06-18
影响因子：
4.8
通讯作者：
Houghton, Janet A.
中科院分区：
文献类型：
--
作者：
Jani, Tanvi S.;DeVecchio, Jennifer;Houghton, Janet A.
结直肠癌是美国第三大常见恶性肿瘤。包括奥沙利铂（L-OHP）在内的治疗方法的适度进展使中位生存率达到22个月，耐药性仍然是一个重要的障碍。肿瘤坏死因子相关凋亡诱导配体（TRAIL）正在进行临床评价。虽然人类结肠癌表达TRAIL受体，但它们也可以表现出TRAIL抗性。组成性NF-κ B活化与对TRAIL和细胞毒性剂的抗性有关。我们已经证明了组成性NF-κ B激活在六个人结肠癌细胞系中的五个，这种激活被奎纳克林抑制。奎纳克林诱导结肠癌细胞凋亡，增强TRAIL对RKO和HT 29细胞的细胞毒活性，增强L-OHP对HT 29细胞的细胞毒活性。类似地，I κ B α突变体（I κ B α M）的过表达或用IKK抑制剂BMS-345541处理也使这些细胞对TRAIL和1-OHP敏感。重要的是，奎纳克林预处理2小时导致c-FLIP和Mcl-1表达降低，这两种蛋白被确定为NF-κ B的转录靶点。延长暴露24小时奎纳克林没有进一步敏感这些细胞的TRAIL或L-OHP诱导的细胞死亡，但是，曝光引起的下调额外的NF-κ B依赖性生存因子。短发夹RNA介导的c-FLIP或Mcl-1的敲低显著地使这些细胞对TRAIL和L-OHP敏感。综上所述，数据表明NF-κ B在结肠癌细胞系和NF-κ B中是组成性活性的，并且其下游靶点可能构成开发针对该疾病的治疗方法的重要靶点
Colorectal cancer is the third most common malignancy in the United States. Modest advances with therapeutic approaches that include oxaliplatin (L-OHP) have brought the median survival rate to 22 months, with drug resistance remaining a significant barrier. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is undergoing clinical evaluation. Although human colon carcinomas express TRAIL receptors, they can also demonstrate TRAIL resistance. Constitutive NF-kappa B activation has been implicated in resistance to TRAIL and to cytotoxic agents. We have demonstrated constitutive NF-kappa B activation in five of six human colon carcinoma cell lines; this activation is inhibited by quinacrine. Quinacrine induced apoptosis in colon carcinomas and potentiated the cytotoxic activity of TRAIL in RKO and HT29 cells and that of L-OHP in HT29 cells. Similarly, overexpression of I kappa B alpha mutant (I kappa B alpha M) or treatment with the IKK inhibitor, BMS-345541, also sensitized these cells to TRAIL and l-OHP. Importantly, 2 h of quinacrine pretreatment resulted in decreased expression of c-FLIP and Mcl-1, which were determined to be transcriptional targets of NF-kappa B. Extended exposure for 24 h to quinacrine did not further sensitize these cells to TRAIL- or L-OHP-induced cell death; however, exposure caused the down-regulation of additional NF-kappa B-dependent survival factors. Short hairpin RNA-mediated knockdown of c-FLIP or Mcl-1 significantly sensitized these cells to TRAIL andL-OHP. Taken together, data demonstrate that NF-kappa B is constitutively active in colon cancer cell lines and NF-kappa B, and its downstream targets may constitute an important target for the development of therapeutic approaches against this disease