PDF(Pubmed)
Abstract：
Although colorectal cancer (CRC) treatment has seen a remarkable improvement in the recent years, many patients will develop metastasis due to the resistance of cancer cells to chemotherapeutics. Targeting mechanisms driving the resistance of CRC cells to treatment would significantly reduce cases of metastasis and death. Induction of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a direct target of the Wnt/β-catenin signaling pathway, might promote resistance of CRC cells to treatment via activation of anti-apoptotic pathways and induction of the multidrug resistance (MDR1) membrane transporter that pumps drugs out of the cells. We hypothesized that inhibition of IGF2BP1 will sensitize CRC cells to chemotherapeutics. We used CRC cell lines with different status of activation of Wnt signaling to show that inhibition of IGF2BP1 potentiates the anti-growth and anti-proliferative effects of chemotherapeutics on CRC cells with activated Wnt/β-catenin signaling pathway. We observed that the inhibition of IGF2BP1 significantly increases apoptosis in the same cells. A remarkable reduction in the migratory capability of those cells was noted as well. We found that inhibition of IGF2BP1 is sufficient to decrease the resistance of chemotherapy-resistant cancer cells with activated Wnt/β-catenin signaling pathway. These findings portray IGF2BP1 as a good candidate for CRC therapy.
摘要：
尽管近年来结直肠癌（CRC）的治疗有了显著的改善，由于癌细胞对化学疗法的抗性，许多患者会发生转移。驱动CRC细胞对治疗的抗性的靶向机制将显著减少转移和死亡的病例。胰岛素样生长因子2mRNA结合蛋白1（IGF2BP1）的诱导，Wnt/β-catenin信号通路的直接靶点，可能通过激活抗凋亡途径和诱导将药物泵出细胞的多药耐药（MDR1）膜转运蛋白来促进CRC细胞对治疗的抗性。我们假设IGF2BP1的抑制将使CRC细胞对化学疗法敏感。我们使用了具有不同Wnt信号激活状态的CRC细胞系，以显示IGF2BP1的抑制增强了化疗剂对具有激活的Wnt/β-catenin信号通路的CRC细胞的抗生长和抗增殖作用。我们观察到IGF2BP1的抑制显著增加相同细胞中的凋亡。还注意到这些细胞的迁移能力的显著降低。我们发现抑制IGF2BP1足以降低具有激活的Wnt/β-catenin信号通路的化疗耐药癌细胞的耐药性。这些发现将IGF2BP1描述为CRC治疗的良好候选者。
