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The cell-penetrating FOXM1 N-terminus (M1-138) demonstrates potent inhibitory effects on cancer cells by targeting FOXM1 and FOXM1-interacting factor SMAD3.
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.32693
Zhenwang Zhang 1 , Huitong Bu 1 , Jingwei Yu 1 , Yan Chen 1 , Chaozhu Pei 1 , Li Yu 1 , Xiaoqin Huang 1 , Guixiang Tan 1 , Yongjun Tan 1
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.32693
Zhenwang Zhang 1 , Huitong Bu 1 , Jingwei Yu 1 , Yan Chen 1 , Chaozhu Pei 1 , Li Yu 1 , Xiaoqin Huang 1 , Guixiang Tan 1 , Yongjun Tan 1
Affiliation
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Transcription factor FOXM1 is involved in stimulating cell proliferation, enhancing DNA damage repair, promoting metastasis of cancer cells, and the inhibition of FOXM1 has been shown to prevent the initiation and progression of multiple cancers and FOXM1 is considered to be an effective target for tumor therapeutic drug development. The N-terminus of FOXM1 has been found to prevent transcriptional activities of FOXM1 and to mediate the interaction between FOXM1 and SMAD3.
METHODS
A recombinant FOXM1 N-terminal domain (1-138aa) fused with a nine arginine cell-penetrating peptide is produced with an E. coli expression system and named as M1-138. The effects of M1-138 on the proliferation, migration, and tumorigenic ability of cancer cells are analyzed in vitro with cell counting, transwell assays, and colony formation assays. Electrophoretic mobility shift assays (EMSAs) and Luciferase activity assays are used to test the DNA binding ability and transcriptional activity of transcription factors. The levels of mRNAs and proteins are measured by quantitative-PCR, Western blotting or Immunohistochemistry. The interactions among proteins are analyzed with Pull-down and Co-immunoprecipitation (Co-IP) assays. The nude mouse engrafted tumor models are used to test the inhibitory effects of M1-138 in vivo.
RESULTS
M1-138 diminishes the proliferation and migration abilities of cancer cells through binding to FOXM1 and FOXM1-interacting factor SMAD3, and consequently attenuating FOXM1 transcriptional activities from both direct and indirect FOXM1-promoter binding mechanisms and interfering with the interaction between FOXM1 and SMAD3. Treatment of M1-138 prevents tumorigenicity of cancer cells and inhibits tumor growth in nude mouse xenograft models with no obvious signs of toxicity.
CONCLUSION
M1-138 is a promising drug candidate for the development of anti-cancer therapeutics targeting FOXM1 and SMAD3.
中文翻译：
穿透细胞的FOXM1 N末端（M1-138）通过靶向FOXM1和FOXM1相互作用因子SMAD3表现出对癌细胞的有效抑制作用。
转录因子FOXM1参与刺激细胞增殖，增强DNA损伤修复，促进癌细胞转移，并且对FOXM1的抑制作用已显示可预防多种癌症的发生和发展，并且FOXM1被认为是治疗肿瘤的有效靶标药物开发。已发现FOXM1的N端可阻止FOXM1的转录活性并介导FOXM1与SMAD3之间的相互作用。方法用大肠杆菌表达系统制备融合有九个精氨酸穿透细胞肽的重组FOXM1 N末端结构域（1-138aa），并将其命名为M1-138。M1-138对癌细胞的增殖，迁移和致瘤能力的影响通过细胞计数，transwell分析和集落形成分析进行了体外分析。电泳迁移率迁移分析（EMSA）和萤光素酶活性分析用于测试转录因子的DNA结合能力和转录活性。通过定量PCR，蛋白质印迹或免疫组织化学测量mRNA和蛋白质的水平。蛋白质之间的相互作用可通过下拉法和免疫共沉淀法（Co-IP）进行分析。使用裸鼠移植的肿瘤模型来测试M1-138在体内的抑制作用。结果M1-138通过与FOXM1和FOXM1相互作用因子SMAD3结合而降低了癌细胞的增殖和迁移能力，因此减弱了直接和间接FOXM1启动子结合机制的FOXM1转录活性，并干扰了FOXM1和SMAD3之间的相互作用。在裸鼠异种移植模型中，M1-138的治疗可防止癌细胞的致瘤性并抑制肿瘤的生长，而没有明显的毒性迹象。结论M1-138是开发针对FOXM1和SMAD3的抗癌治疗药物的有希望的候选药物。
更新日期：2019-01-01
中文翻译：
穿透细胞的FOXM1 N末端（M1-138）通过靶向FOXM1和FOXM1相互作用因子SMAD3表现出对癌细胞的有效抑制作用。
转录因子FOXM1参与刺激细胞增殖，增强DNA损伤修复，促进癌细胞转移，并且对FOXM1的抑制作用已显示可预防多种癌症的发生和发展，并且FOXM1被认为是治疗肿瘤的有效靶标药物开发。已发现FOXM1的N端可阻止FOXM1的转录活性并介导FOXM1与SMAD3之间的相互作用。方法用大肠杆菌表达系统制备融合有九个精氨酸穿透细胞肽的重组FOXM1 N末端结构域（1-138aa），并将其命名为M1-138。M1-138对癌细胞的增殖，迁移和致瘤能力的影响通过细胞计数，transwell分析和集落形成分析进行了体外分析。电泳迁移率迁移分析（EMSA）和萤光素酶活性分析用于测试转录因子的DNA结合能力和转录活性。通过定量PCR，蛋白质印迹或免疫组织化学测量mRNA和蛋白质的水平。蛋白质之间的相互作用可通过下拉法和免疫共沉淀法（Co-IP）进行分析。使用裸鼠移植的肿瘤模型来测试M1-138在体内的抑制作用。结果M1-138通过与FOXM1和FOXM1相互作用因子SMAD3结合而降低了癌细胞的增殖和迁移能力，因此减弱了直接和间接FOXM1启动子结合机制的FOXM1转录活性，并干扰了FOXM1和SMAD3之间的相互作用。在裸鼠异种移植模型中，M1-138的治疗可防止癌细胞的致瘤性并抑制肿瘤的生长，而没有明显的毒性迹象。结论M1-138是开发针对FOXM1和SMAD3的抗癌治疗药物的有希望的候选药物。
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