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首页> 外文期刊>Journal of cellular physiology. >Targeting Wnt/p-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia
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Targeting Wnt/p-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia

机译：针对Wnt / p-catenin和PI3K / Akt / mTOR通路在t细胞急性淋巴细胞白血病

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摘要

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, β-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β-catenin pathway through ICG-001, a CBP/β-catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK-474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T-ALL cells. ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β-catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-ALL settings.
机译：t细胞急性淋巴细胞白血病(t)是一个激进的血液疾病,结果从克隆t细胞转化体细胞。PI3K / Akt /机械的雷帕霉素靶(mTOR)和规范Wnt /β连环蛋白信号通路在t细胞发育和起到至关重要的作用健康和白血病干细胞的自我更新。值得注意的是,β连环蛋白是转录监管机构几个基因在癌细胞增殖和生存。属于畸变的组件提到的网络导致t发病机理。途径可以代表一个创新的策略血液恶性肿瘤。结合目标Wnt /β连环蛋白通路通过协调小组- 001,CBP /β连环蛋白转录抑制剂,PI3K / Akt / mTOR的轴zstk - 474, PI3K抑制剂,表达下调增殖、生存和单独活动t细胞。细胞毒性效应,当组合在一起时,诱导凋亡的显著增加细胞。的差别,对这些Wnt /β连环蛋白和PI3K / Akt / mTOR通路。在缺氧条件下,模拟确认白血病干细胞是骨髓领域认为驻留。强调潜在的有前途的治疗组成的cotargeting Wnt /β连环蛋白和mTOR / PI3K / Akt通路中所有设置。

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