PTEN regulates BCRP/ABCG2 and the side population through the PI3K/Akt pathway in chronic myeloid leukemia.
PTEN regulates BCRP/ABCG2 and the side population through the PI3K/Akt pathway in chronic myeloid leukemia.
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DOI：
10.1371/journal.pone.0088298
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zeng H
中科院分区：
文献类型：
--
作者：
Huang FF;Zhang L;Wu DS;Yuan XY;Yu YH;Zhao XL;Chen FP;Zeng H
被称为“侧群”（SP）的一小群癌症干细胞已被证明是许多实体瘤持续存在的原因。然而，SP在白血病发病机制中的作用仍存在争议。白血病干细胞对靶向治疗（如酪氨酸激酶抑制剂（TKI））的抗性导致慢性髓性白血病（CML）的治疗失败或难治性/复发性疾病。药物泵，ATP结合盒亚家族G成员2（ABCG 2），是众所周知的SP的特异性标志物，并且可以由包括PI 3 K/Akt通路在内的若干通路控制。我们的数据表明，与野生型K562细胞相比，较高的ABCG 2+细胞百分比对应于K562/ABCG 2（ABCG 2过表达）和K562/IMR（伊马替尼耐药）细胞中较高的SP分数，这些细胞表现出增强的耐药性，沿着下调的10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）和活化的磷酸化Akt（p-Akt）。PI 3 K抑制剂LY 294002和mTOR抑制剂雷帕霉素都可以消除PTEN和p-Akt的下调。此外，在CML患者的加速期/急变期（AP/BP），增加SP表型，而不是ABCG 2表达伴随着PTEN蛋白的丢失和p-Akt表达上调。这些结果提示，PTEN可能通过PI 3 K/Akt通路调控ABCG 2和SP的表达，这可能是一种潜在的针对CML干细胞的有效策略。
A small population of cancer stem cells named the “side population” (SP) has been demonstrated to be responsible for the persistence of many solid tumors. However, the role of the SP in leukemic pathogenesis remains controversial. The resistance of leukemic stem cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ATP-binding cassette sub-family G member 2 (ABCG2), is well known as a specific marker of the SP and could be controlled by several pathways, including the PI3K/Akt pathway. Our data demonstrated that compared with wild-type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated phosphatase and tensin homologue deleted on chromosome -10 (PTEN) and activated phosphorylated-Akt (p-Akt). PTEN and p-Akt downregulation could be abrogated by both the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin. Moreover, in CML patients in the accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression was accompanied by the loss of PTEN protein and the up-regulation of p-Akt expression. These results suggested that the expression of ABCG2 and the SP may be regulated by PTEN through the PI3K/Akt pathway, which would be a potentially effective strategy for targeting CML stem cells.
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