Arsenic trioxide enhances the chemotherapeutic efficiency of cisplatin in cholangiocarcinoma cells via inhibiting the 14-3-3ε-mediated survival mechanism

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.

Arnicolide C Suppresses Tumor Progression by Targeting 14-3-3θ in Breast Cancer

“…Studies have shown that 14-3-3 proteins are essential for cancer development [24][25][26][27][28][29]. 14-3-3 proteins are ubiquitously expressed in eukaryotic cells, and there are seven main protein isoforms in mammals [30].…”

“…14-3-3 proteins can bind to other proteins [ 17 , 18 ] and participate in various biological activities, including signal transduction, cell cycle progression, apoptosis, and enzyme activity regulation [ 19 , 20 , 21 , 22 , 23 ]. Studies have shown that 14-3-3 proteins are essential for cancer development [ 24 , 25 , 26 , 27 , 28 , 29 ]. 14-3-3 proteins are ubiquitously expressed in eukaryotic cells, and there are seven main protein isoforms in mammals [ 30 ].…”

Arsenic trioxide-loaded nanoparticles enhance the chemosensitivity of gemcitabine in pancreatic cancer via the reversal of pancreatic stellate cell desmoplasia by targeting the AP4/galectin-1 pathway

“…26,27 Extensive studies have shown that ATO is beneficial for several solid cancers, such as liver carcinoma, colorectal cancer, prostatic cancer and pancreatic cancer. 28,29 ATO can be used as a chemotherapeutic sensitizer to enhance the chemotherapeutic efficiency of cisplatin or 5-fluorouracil in cholangiocarcinoma cells 30,31 and to increase the anticancer (apoptotic) activity in oral squamous cell carcinoma, 32 cisplatin-resistant non-small-cell lung carcinoma 33 and head and neck squamous cell cancer. 34 Our previous study has shown that ATO is a promising anticancer agent in PDAC.…”