Arsenic trioxide enhances the chemotherapeutic efficiency of cisplatin in cholangiocarcinoma cells via inhibiting the 14-3-3ε-mediated survival mechanism
Open Access
- 21 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death Discovery
- Vol. 6 (1), 1-10
- https://doi.org/10.1038/s41420-020-00330-x
Abstract
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.Keywords
This publication has 46 references indexed in Scilit:
- Cholangiocarcinoma: novel therapeutic targetsEmerging Therapeutic Targets, 2020
- Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical TrialJAMA Oncology, 2019
- Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cellsNature Communications, 2018
- Arsenic trioxide: insights into its evolution to an anticancer agentJBIC Journal of Biological Inorganic Chemistry, 2018
- Cholangiocarcinoma — evolving concepts and therapeutic strategiesNature Reviews Clinical Oncology, 2017
- Current management of newly diagnosed acute promyelocytic leukemiaAnnals of Oncology, 2016
- Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cellsToxicology Letters, 2014
- Inhibition of the Cancer Stem Cells-Like Properties by Arsenic Trioxide, Involved in the Attenuation of Endogenous Transforming Growth Factor Beta SignalToxicological Sciences, 2014
- Guidelines for the diagnosis and management of intrahepatic cholangiocarcinomaJournal of Hepatology, 2014
- Pathogenesis, Diagnosis, and Management of CholangiocarcinomaGastroenterology, 2013