Glycogen synthase kinase-3β inhibition depletes the population of prostate cancer stem/progenitor-like cells and attenuates metastatic growth.
Glycogen synthase kinase-3β inhibition depletes the population of prostate cancer stem/progenitor-like cells and attenuates metastatic growth.
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DOI：
10.18632/oncotarget.1510
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发表时间：
2014-10-15
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影响因子：
--
通讯作者：
van der Pluijm G
中科院分区：
文献类型：
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作者：
Kroon J;in 't Veld LS;Buijs JT;Cheung H;van der Horst G;van der Pluijm G
具有干细胞或祖细胞特性的癌细胞在实体瘤（包括人前列腺的实体瘤）的发生、复发和转移潜力中起关键作用。癌症干细胞通常对常规疗法更具抗性，因此需要表征参与该恶性细胞亚群的形成和/或维持的关键途径。为此，我们鉴定了糖原合成酶激酶-3 β（GSK-3β）作为维持前列腺癌干/祖细胞样细胞的关键激酶，并且GSK-3β的药理学抑制显著降低了该细胞亚群的大小。这是由受损的克隆形成，降低迁移潜力和戏剧性的形态学变化。与我们的体外观察结果一致，在临床前体内模型中，GSK-3β抑制剂治疗导致致瘤性完全丧失和转移潜力降低。这些观察到的抗肿瘤作用似乎在很大程度上不依赖于Wnt，因为同时Wnt抑制不会逆转GSK-3β阻断的观察到的抗肿瘤作用。我们发现GSK-3β的活性与细胞骨架蛋白F-actin有关，抑制GSK-3β可导致F-actin聚合障碍。这可能是GSK-3β抑制对前列腺癌迁移的显著影响的基础。此外，GSK-3β抑制导致几种整合素类型的表达强烈降低，包括癌症干细胞相关的α2β1整合素。总之，我们的机制观察突出了GSK-3β活性在前列腺癌干性中的重要性，并可能促进晚期前列腺癌新疗法的开发。
Cancer cells with stem or progenitor properties play a pivotal role in the initiation, recurrence and metastatic potential of solid tumors, including those of the human prostate. Cancer stem cells are generally more resistant to conventional therapies thus requiring the characterization of key pathways involved in the formation and/or maintenance of this malignant cellular subpopulation. To this end, we identified Glycogen Synthase Kinase-3β (GSK-3β) as a crucial kinase for the maintenance of prostate cancer stem/progenitor-like cells and pharmacologic inhibition of GSK-3β dramatically decreased the size of this cellular subpopulation. This was paralleled by impaired clonogenicity, decreased migratory potential and dramatic morphological changes. In line with our in vitro observations, treatment with a GSK-3β inhibitor leads to a complete loss of tumorigenicity and a decrease in metastatic potential in preclinical in vivo models. These observed anti-tumor effects appear to be largely Wnt-independent as simultaneous Wnt inhibition does not reverse the observed antitumor effects of GSK-3β blockage. We found that GSK-3β activity is linked to cytoskeletal protein F-actin and inhibition of GSK-3β leads to disturbance of F-actin polymerization. This may underlie the dramatic effects of GSK-3β inhibition on prostate cancer migration. Furthermore, GSK-3β inhibition led to strongly decreased expression of several integrin types including the cancer stem cell-associated α2β1 integrin. Taken together, our mechanistic observations highlight the importance of GSK-3β activity in prostate cancer stemness and may facilitate the development of novel therapy for advanced prostate cancer.