Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model.
Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model.
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DOI：
10.18632/oncotarget.4656
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发表时间：
2015-09-22
期刊：
影响因子：
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通讯作者：
Sarkar D
中科院分区：
文献类型：
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作者：
Rajasekaran D;Siddiq A;Willoughby JL;Biagi JM;Christadore LM;Yunes SA;Gredler R;Jariwala N;Robertson CL;Akiel MA;Shen XN;Subler MA;Windle JJ;Schaus SE;Fisher PB;Hansen U;Sarkar D
肝细胞癌是一种致死性恶性肿瘤，死亡率高，预后差。癌基因转录因子LSF在肝癌的发生发展中起重要作用。LSF的小分子抑制剂，因子喹啉酮抑制剂1（FQ I 1），显著抑制裸鼠中的人HCC异种移植物而不损害正常细胞。在这里，我们评估了抑制剂，抑制剂，抑制内源性肝癌发生的疗效。通过注射N-亚硝基二乙胺（DEN），然后在肿瘤形成后用ALIB 1或ALIB 2处理，在肝细胞特异性过表达c-myc（Alb/c-myc）的转基因小鼠中诱导HCC。LSF抑制剂显著降低Alb/c-myc小鼠的肿瘤负荷，同时相应降低增殖和血管生成。有趣的是，在体外用LSF抑制剂处理人HCC细胞导致有丝分裂停滞，伴随着CyclinB 1的增加。CyclinB 1诱导的环己酰亚胺或CDK 1活性的Roscovitine抑制显着阻止了RNAi诱导的有丝分裂阻滞。在用FQI处理后还观察到细胞凋亡的显著诱导。LSF抑制、有丝分裂停滞和通过RNAi 1诱导细胞凋亡的这些作用提供了这些抑制剂消除HCC细胞的多种途径。LSF抑制剂可能是单独或与现有疗法组合用于HCC的高效且有效的治疗剂。
Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality and poor prognosis. Oncogenic transcription factor Late SV40 Factor (LSF) plays an important role in promoting HCC. A small molecule inhibitor of LSF, Factor Quinolinone Inhibitor 1 (FQI1), significantly inhibited human HCC xenografts in nude mice without harming normal cells. Here we evaluated the efficacy of FQI1 and another inhibitor, FQI2, in inhibiting endogenous hepatocarcinogenesis. HCC was induced in a transgenic mouse with hepatocyte-specific overexpression of c-myc (Alb/c-myc) by injecting N-nitrosodiethylamine (DEN) followed by FQI1 or FQI2 treatment after tumor development. LSF inhibitors markedly decreased tumor burden in Alb/c-myc mice with a corresponding decrease in proliferation and angiogenesis. Interestingly, in vitro treatment of human HCC cells with LSF inhibitors resulted in mitotic arrest with an accompanying increase in CyclinB1. Inhibition of CyclinB1 induction by Cycloheximide or CDK1 activity by Roscovitine significantly prevented FQI-induced mitotic arrest. A significant induction of apoptosis was also observed upon treatment with FQI. These effects of LSF inhibition, mitotic arrest and induction of apoptosis by FQI1s provide multiple avenues by which these inhibitors eliminate HCC cells. LSF inhibitors might be highly potent and effective therapeutics for HCC either alone or in combination with currently existing therapies.