Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/β-catenin/CBP pathway
Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/β-catenin/CBP pathway
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DOI：
10.1002/ijc.28341
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发表时间：
2014-01-01
影响因子：
6.4
通讯作者：
Goldkorn, Amir
中科院分区：
文献类型：
--
作者：
He, Kaijie;Xu, Tong;Goldkorn, Amir
癌症的发生和发展归因于新发现的称为癌症干细胞的自我更新、高度致瘤性、耐药性肿瘤细胞的亚群。最近，我们和其他人报道了一种新的表型可塑性，其中高度致瘤性的耐药细胞群不仅可能来自预先存在的癌症干细胞样群体，而且可能来自缺乏这些特性的癌细胞。在目前的研究中，我们假设这种新发现的表型可塑性可能是由PI 3 K/Akt和Wnt/-catenin信号传导介导的，这些信号传导通路先前与致癌、多能性和耐药性有关。使用GFP表达，Hoechst染料排斥和荧光激活细胞分选（FACS）的癌细胞系，我们确定和跟踪癌干细胞样侧群（SP）的癌细胞的特征在于高致瘤性和耐药性。我们发现，药物抑制或基因耗竭PI 3 K和AKT显着减少非侧群（NSP）细胞转化为癌症干细胞样SP细胞的自发转化，而PI 3 K/Akt激活相反增强NSP到SP的转换。PI 3 K/AKT信号通过下游的GSK 3磷酸化介导，其导致β-catenin的激活和积累。因此，GSK 3或β-catenin的药理学或遗传扰动显著影响NSP向SP的转化。进一步下游，β-catenin对NSP-SP平衡的影响取决于其与CBP（KAT 3家族共激活剂）的相互作用。这些研究提供了一种机制模型，其中PI 3 K/Akt/β-catenin/CBP信号转导介导了耐药性、高度致瘤性状态的表型可塑性。因此，靶向这一通路对于克服由癌症干细胞样表型引起的治疗耐药性和疾病进展具有独特的潜力。癌细胞自发转化为癌干细胞样表型和从癌干细胞样表型转化的能力可能是耐药性和癌症进展的主要因素。虽然一直缺乏一个机制的解释，新的研究结果表明，这一显着的过程是由PI 3 K/Akt和-catenin/CBP信号通路。药理学抑制或这些途径中的分子的遗传破坏导致体外乳腺癌和膀胱癌细胞的表型可塑性显著降低。结果表明，这些途径的缓解可能是克服治疗抵抗和疾病进展的关键。
Cancer initiation and progression have been attributed to newly discovered subpopulations of self-renewing, highly tumorigenic, drug-resistant tumor cells termed cancer stem cells. Recently, we and others reported a new phenotypic plasticity wherein highly tumorigenic, drug-resistant cell populations could arise not only from pre-existing cancer stem-like populations but also from cancer cells lacking these properties. In the current study, we hypothesized that this newfound phenotypic plasticity may be mediated by PI3K/Akt and Wnt/-catenin signaling, pathways previously implicated in carcinogenesis, pluripotency and drug resistance. Using GFP expression, Hoechst dye exclusion and fluorescence activated cell sorting (FACS) of cancer cell lines, we identified and tracked cancer stem-like side populations (SP) of cancer cells characterized by high tumorigenicity and drug resistance. We found that pharmacological inhibition or genetic depletion of PI3K and AKT markedly reduced the spontaneous conversion of nonside population (NSP) cells into cancer stem-like SP cells, whereas PI3K/Akt activation conversely enhanced NSP to SP conversion. PI3K/AKT signaling was mediated through downstream phosphorylation of GSK3, which led to activation and accumulation of -catenin. Accordingly, pharmacological or genetic perturbation of GSK3 or -catenin dramatically impacted conversion of NSP to SP. Further downstream, -catenin's effects on NSP-SP equilibrium were dependent upon its interaction with CBP, a KAT3 family coactivator. These studies provide a mechanistic model wherein PI3K/Akt/-catenin/CBP signaling mediates phenotypic plasticity in and out of a drug-resistant, highly tumorigenic state. Therefore, targeting this pathway has unique potential for overcoming the therapy resistance and disease progression attributed to the cancer stem-like phenotype.What's new? The ability of cancer cells to spontaneously convert to and from a cancer stem-like phenotype may be a major factor in drug resistance and cancer progression. While a mechanistic explanation has been lacking, new findings reported here suggest that this remarkable process is governed by the PI3K/Akt and -catenin/CBP signaling pathways. Pharmacological inhibition or genetic disruption of molecules in these pathways led to dramatic reductions in the phenotypic plasticity of breast and bladder cancer cells in vitro. The results indicate that the pathways' mitigation could be key to overcoming therapy resistance and disease progression.