Cholangiocarcinoma (CCA) is the second most frequent primary liver carcinoma with high degrees of malignancy and mortality. Chemotherapy plays a key role in the treatment of CCA, however, the low chemotherapeutic efficiency leads to a bottleneck. So unraveling the potential mechanisms to enhance the efficiency (reduced the dosage and enhanced the effects of chemotherapy drugs) and identifying alternative therapeutic strategies in CCA are urgently needed. Here, we found that, in CCA cells, when cisplatin (CDDP) displayed anti-tumor effects, it activated 14-3-3ε simultaneously, which in turn formed a survival mechanism via the phosphorylation of phosphatidylinositol 3-kinase/protein kinase B (PI-3K/Akt). However, low concentrations of arsenic trioxide (ATO) could disrupt such survival mechanism and enhanced the efficiency. For the molecular mechanisms, ATO attenuated 14-3-3ε at both transcriptional and post-transcriptional (ubiquitination degradation) levels. Such repressive effect blocked the activation of PI-3K/Akt, and its downstream anti-apoptotic factors, B-cell lymphoma 2 (Bcl-2), and survivin. Collectively, our present study revealed that the synergistic effects of ATO and CDDP could be a novel approach for enhancing the efficiency, which provides an innovative therapeutic vision for the treatment of CCA.

胆管癌（CCA）是第二常见的原发性肝癌，其恶性程度和死亡率很高。化疗在CCA的治疗中发挥着关键作用，但化疗效率低下却成为治疗瓶颈。因此，迫切需要揭示提高 CCA 效率的潜在机制（减少化疗药物的剂量并增强化疗药物的效果）并确定替代治疗策略。在这里，我们发现，在CCA细胞中，当顺铂（CDDP）发挥抗肿瘤作用时，它同时激活14-3-3ε，进而通过磷脂酰肌醇3-激酶/蛋白激酶B的磷酸化形成生存机制。 PI-3K/Akt）。然而，低浓度的三氧化二砷（ATO）可以破坏这种生存机制并提高效率。对于分子机制，ATO 在转录和转录后（泛素化降解）水平上减弱 14-3-3ε。这种抑制作用阻断了 PI-3K/Akt 及其下游抗凋亡因子、B 细胞淋巴瘤 2 (Bcl-2) 和生存素的激活。总的来说，我们目前的研究表明，ATO 和 CDDP 的协同作用可能是一种提高效率的新方法，为 CCA 的治疗提供了创新的治疗愿景。