Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence
Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence
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DOI：
10.1186/s12885-020-07039-1
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发表时间：
2020-06-15
期刊：
影响因子：
3.8
通讯作者：
Hansen, Ulla
中科院分区：
文献类型：
--
作者：
Willoughby, Jennifer L. S.;George, Kelly;Hansen, Ulla
背景LSF癌基因（TFCP 2编码）已被提出作为多种癌症的新的治疗靶点。患者肿瘤中LSF过表达与不良预后相关，特别是对于肝细胞癌和结肠直肠癌。这些疾病有限的治疗结果和令人失望的临床结果，特别是在靶向细胞受体和激酶的分子靶向治疗中的肝细胞癌，强调了对分子靶向新机制的需求。LSF小分子抑制剂，因子喹啉酮抑制剂（FQ），在多个临床前模型中表现出强大的抗肿瘤活性，没有可观察到的toxicity.MethodsTo了解LSF抑制剂如何影响癌细胞增殖，我们表征了LSF活性丧失导致的细胞表型。细胞增殖和细胞周期的进展进行了分析，使用HeLa细胞作为模型癌细胞系响应于MARI 1。通过延时显微镜或通过细胞群的批量同步化研究细胞周期进程，以确保结果解释的准确性。为了测试靶向LSF的生物学特异性的MARI 1，结果进行了比较治疗后与MARI 1或siRNA靶向LSF.ResultsHighly相似的细胞表型观察后与MARI 1和siRNA靶向LSF治疗。沿着对两种细胞生物标志物的相似影响，通过任一机制抑制LSF活性诱导了中期前的强烈延迟或停滞，因为细胞通过有丝分裂进行，染色体浓缩但未对齐。在这两种情况下，这种有丝分裂破坏导致细胞分裂不当，导致多种结果：多核，细胞凋亡，和细胞senescence.ConclusionsThese数据强烈支持，观察到的细胞表型后，ESTI 1治疗是由于特别是LSF活动的损失。小分子或siRNA对LSF的特异性抑制导致严重的有丝分裂缺陷，导致细胞死亡或衰老-这是对抗癌症所期望的结果。总之，这些发现证实LSF是一个有希望的癌症治疗靶点。此外，这项研究为开发RNAi或其他LSF抑制策略作为治疗LSF相关癌症提供了进一步的支持，这些癌症具有高度未满足的医疗需求。
BackgroundThe oncogene LSF (encoded by TFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal cancer. The limited treatment outcomes for these diseases and disappointing clinical results, in particular, for hepatocellular carcinoma in molecularly targeted therapies targeting cellular receptors and kinases, underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple pre-clinical models, with no observable toxicity.MethodsTo understand how the LSF inhibitors impact cancer cell proliferation, we characterized the cellular phenotypes that result from loss of LSF activity. Cell proliferation and cell cycle progression were analyzed, using HeLa cells as a model cancer cell line responsive to FQI1. Cell cycle progression was studied either by time lapse microscopy or by bulk synchronization of cell populations to ensure accuracy in interpretation of the outcomes. In order to test for biological specificity of targeting LSF by FQI1, results were compared after treatment with either FQI1 or siRNA targeting LSF.ResultsHighly similar cellular phenotypes are observed upon treatments with FQI1 and siRNA targeting LSF. Along with similar effects on two cellular biomarkers, inhibition of LSF activity by either mechanism induced a strong delay or arrest prior to metaphase as cells progressed through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption in both cases resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence.ConclusionsThese data strongly support that cellular phenotypes observed upon FQI1 treatment are due specifically to the loss of LSF activity. Specific inhibition of LSF by either small molecules or siRNA results in severe mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings confirm that LSF is a promising target for cancer treatment. Furthermore, this study provides further support for developing FQIs or other LSF inhibitory strategies as treatment for LSF-related cancers with high unmet medical needs.