Konishi Jun, Kawaguchi Keiko S, Vo Huan, Haruki Nobuhiro, Gonzalez Adriana, Carbone David P, Dang Thao P
Division of Hematology and Medical Oncology and Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cancer Res. 2007 Sep 1;67(17):8051-7. doi: 10.1158/0008-5472.CAN-07-1022.
Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms. Genes that are important for normal differentiation play a role in cancer when their normal functions became dysregulated. Notch signaling has been shown to promote and maintain survival of many types of cancers, and we previously have shown that Notch3 plays an important role in lung cancer. In this study, we showed that a high percentage of lung cancer lines expressed Jagged1, Notch receptors, and their transcriptional target genes (HES1, Hey1), suggesting that the Notch pathway plays an important role in lung cancer biology. Thus, inhibition of Notch receptor activation represents a compelling treatment strategy. Notch activation requires proteolytic cleavage of the receptor by gamma-secretase protein complex. In this study, we determined the ability of MRK-003, a gamma-secretase inhibitor, to inhibit Notch3 signaling, growth, and apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models. We also found that MRK-003 inhibited Notch3 signaling, reduced tumor cell proliferation, inhibited serum independence, and induced apoptosis. This drug had no effect when Notch3 expression was knocked down using small interfering RNA (siRNA), suggesting that the observed effects were mediated by specific action on this receptor. In conclusion, these results support the hypothesis that inhibition of Notch activation using a gamma-secretase inhibitor represents a potential new approach for the targeted therapy of lung cancer.
Notch受体是许多多细胞生物中通过控制细胞命运决定来调节发育的关键因子。对正常分化至关重要的基因，当其正常功能失调时，会在癌症中发挥作用。Notch信号通路已被证明可促进和维持多种癌症的存活，我们之前也已表明Notch3在肺癌中起重要作用。在本研究中，我们发现高比例的肺癌细胞系表达Jagged1、Notch受体及其转录靶基因（HES1、Hey1），这表明Notch信号通路在肺癌生物学中起重要作用。因此，抑制Notch受体激活是一种有吸引力的治疗策略。Notch激活需要γ-分泌酶蛋白复合物对受体进行蛋白水解切割。在本研究中，我们使用小鼠异种移植模型，确定了γ-分泌酶抑制剂MRK-003在体外和体内抑制肺癌细胞系中Notch3信号传导、生长和凋亡的能力。我们还发现MRK-003抑制Notch3信号传导，减少肿瘤细胞增殖，抑制血清非依赖性，并诱导凋亡。当使用小干扰RNA（siRNA）敲低Notch3表达时，该药物没有效果，这表明观察到的效应是由对该受体的特异性作用介导的。总之，这些结果支持这样的假设，即使用γ-分泌酶抑制剂抑制Notch激活代表了一种针对肺癌的潜在新的靶向治疗方法。
