Oncology Disease Research Unit, Children's Hospital of Mexico, Federico Gomez, Mexico City 06720, Mexico.
Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
Int J Mol Sci. 2024 Jul 16;25(14):7767. doi: 10.3390/ijms25147767.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Current chemotherapy treatment regimens have improved survival rates to approximately 80%; however, resistance development remains the primary cause of treatment failure, affecting around 20% of cases. Some studies indicate that loss of the phosphatase and tensin homolog (PTEN) leads to deregulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, increasing the expression of proteins involved in chemoresistance. PTEN loss results in deregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces hypoxia-inducible factor 1-alpha (HIF-1α) expression in various cancers. Additionally, it triggers upregulation of the Yin Yang 1 (YY1) transcription factor, leading to chemoresistance mediated by glycoprotein p-170 (Gp-170). The aim of this study was to investigate the role of the PTEN/NF-κB axis in YY1 regulation via HIF-1α and its involvement in ALL. A PTEN inhibitor was administered in RS4;11 cells, followed by the evaluation of PTEN, NF-κB, HIF-1α, YY1, and Gp-170 expression, along with chemoresistance assessment. PTEN, HIF-1α, and YY1 expression levels were assessed in the peripheral blood mononuclear cells (PBMC) from pediatric ALL patients. The results reveal that the inhibition of PTEN activity significantly increases the expression of pAkt and NF-κB, which is consistent with the increase in the expression of HIF-1α and YY1 in RS4;11 cells. In turn, this inhibition increases the expression of the glycoprotein Gp-170, affecting doxorubicin accumulation in the cells treated with the inhibitor. Samples from pediatric ALL patients exhibit PTEN expression and higher HIF-1α and YY1 expression compared to controls. PTEN/Akt/NF-κB axis plays a critical role in the regulation of YY1 through HIF-1α, and this mechanism contributes to Gp-170-mediated chemoresistance in pediatric ALL.
急性淋巴细胞白血病 (ALL) 是最常见的儿童癌症。目前的化疗治疗方案已将存活率提高到约 80%；然而，耐药性的发展仍然是治疗失败的主要原因，约 20%的病例受到影响。一些研究表明，磷酸酶和张力蛋白同系物 (PTEN) 的丢失导致磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (Akt) 信号通路的失调，增加了参与化疗耐药的蛋白的表达。PTEN 丢失导致核因子 κB 轻链增强子的激活 B 细胞 (NF-κB) 的失调，并在各种癌症中诱导缺氧诱导因子 1-α (HIF-1α) 的表达。此外，它触发 Yin Yang 1 (YY1) 转录因子的上调，导致糖蛋白 p-170 (Gp-170) 介导的化疗耐药。本研究旨在探讨 PTEN/NF-κB 轴通过 HIF-1α 调节 YY1 的作用及其在 ALL 中的参与。在 RS4;11 细胞中给予 PTEN 抑制剂，然后评估 PTEN、NF-κB、HIF-1α、YY1 和 Gp-170 的表达以及化疗耐药性。评估儿科 ALL 患者外周血单核细胞 (PBMC) 中的 PTEN、HIF-1α 和 YY1 表达水平。结果表明，PTEN 活性的抑制显著增加了 pAkt 和 NF-κB 的表达，这与 RS4;11 细胞中 HIF-1α 和 YY1 表达的增加一致。反过来，这种抑制增加了糖蛋白 Gp-170 的表达，影响了抑制剂处理细胞中阿霉素的积累。与对照组相比，儿科 ALL 患者样本的 PTEN 表达以及 HIF-1α 和 YY1 的表达更高。PTEN/Akt/NF-κB 轴通过 HIF-1α 对 YY1 的调节起着关键作用，这种机制导致儿科 ALL 中 Gp-170 介导的化疗耐药。
