Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway.
Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway.
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Sulfarotene 是一种合成类维生素A，通过抑制 SOS2-RAS 通路克服肝细胞癌的干细胞性和索拉非尼耐药性
DOI：
10.1186/s13046-021-02085-4
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发表时间：
2021-09-04
期刊：
影响因子：
--
通讯作者：
Xia J
中科院分区：
文献类型：
--
作者：
Qi F;Qin W;Zhang Y;Luo Y;Niu B;An Q;Yang B;Shi K;Yu Z;Chen J;Cao X;Xia J
复发性肝细胞癌对索拉非尼表现出较强的耐药性，具有肿瘤干细胞样特性的肿瘤再填充细胞(TRACs)因其高复发率和耐药而被认为是一种有效的治疗策略。我们评价了一种新型的人工合成维甲酸对肝细胞癌干细胞样特性的药理和作用机制，并在肝细胞癌患者来源的异种移植(PDXs)模型中评价了其临床前疗效。结果舒法罗汀在体外选择性抑制肝细胞癌细胞的生长，显著阻止肿瘤细胞的形成和体内的肺转移，且无明显毒性，IC50优于无环类维甲酸和索拉非尼，复发性肝癌对后者表现出明显的耐药性。舒法罗汀促进RARα的表达和激活，从而下调参与RAS激活和信号转导的关键信号介质SOS2，该信号转导涉及多个下游通路。结论本研究证实舒法罗汀是一种选择性抑制肝癌细胞α-SOS2-RAS信号通路的靶点，为晚期肝癌的靶向治疗提供了一种新的靶向策略。
BackgroundRecurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumor-repopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance.MethodsSuppression of TRCs may thus be an effective therapeutic strategy for treating this fatal disease. We evaluated the pharmacology and mechanism of sulfarotene, a new type of synthetic retinoid, on the cancer stem cell-like properties of HCC TRCs, and assessed its preclinical efficacy in models of HCC patient-derived xenografts (PDXs).ResultsSulfarotene selectively inhibited the growth of HCC TRCs in vitro and significantly deterred TRC-mediated tumor formation and lung metastasis in vivo without apparent toxicity, with an IC50superior to that of acyclic retinoid and sorafenib, to which the recurrent HCC exhibits significant resistance at advanced stage. Sulfarotene promoted the expression and activation of RARα, which down-regulated SOS2, a key signal mediator associated with RAS activation and signal transduction involved in multiple downstream pathways. Moreover, sulfarotene selectively inhibited tumorigenesis of HCC PDXs with high expression for SOS2.ConclusionsOur study identified sulfarotene as a selective inhibitor for the TRCs of HCC, which targets a novel RARα-SOS2-RAS signal nexus, shedding light on a new, promising strategy of target therapy for advanced liver cancer.
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影响因子：
11.2
作者：
Li Y;Luo S;Ma R;Liu J;Xu P;Zhang H;Tang K;Ma J;Zhang Y;Liang X;Sun Y;Ji T;Wang N;Huang B
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DOI：
10.1073/pnas.1812963116
发表时间：
2019-02-12
影响因子：
11.1
作者：
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影响因子：
6.4
作者：
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通讯作者：
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影响因子：
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作者：
Matsushima-Nishiwaki, R;Okuno, M;Moriwaki, H
通讯作者：
Moriwaki, H
影响因子：
50.3
作者：
Magee JA;Piskounova E;Morrison SJ
通讯作者：
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