Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14–3-3η/NF-κB feedback loop

Abstract

BackgroundMulti-drug resistance (MDR) is one of the main obstacles for treatment of advanced/recurrent hepatocellular carcinoma (HCC). We have previously identified arsenic trioxide (ATO) as an effective metastasis/angiogenesis inhibitor in HCC. Here, we further found that MDR-HCC cells were more sensitive to ATO.MethodsThe MDR-HCC cells were used as experimental models. Biological functions were investigated using cell transfection, polymerase chain reaction, western blot, southwestern blot, immunostaining, immunoprecipitation plus atomic fluorescence spectrometry, and so on.ResultsThe MDR-HCC cells underwent high oxidative stress condition, and employed adaptive mechanisms for them to survive; while ATO abolished such mechanisms via targeting the 14–3-3η/nuclear factor kappa B (NF-κB) feedback Loop. Briefly, in MDR cells, the increase of ROS activated NF-κB signaling, which transcriptionally activated 14–3-3η. Meanwhile, the activation of NF-κB can be constitutively maintained by 14–3-3η. As a NF-κB inhibitor, ATO transcriptionally inhibited the 14–3-3η mRNA level. Meanwhile, ATO was also validated to directly bind to 14–3-3η, enhancing the degradation of 14–3-3η protein in an ubiquitination-dependent manner. Knockdown of 14–3-3η reduced the ATO-induced reversal extents of drug resistance in MDR cells.Conclusion14–3-3η/NF-κB feedback loop plays an important role in maintaining the MDR phenotype in HCC. Moreover, via targeting such feedback loop, ATO could be considered as a potential molecular targeted agent for the treatment of HCC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1005-y) contains supplementary material, which is available to authorized users.

Mechanism and molecular network of RBM8A-mediated regulation of oxaliplatin resistance in hepatocellular carcinoma via EMT

“…The regulation of noncoding RNAs, such as miR-125 [32], miR-31 [34], H19 [35], and NR2F1 [36], has been shown to be involved in the development and progression of HCC and is involved in tumor resistance. The NF-κB, PI3K/Akt, GSK3β/β-catenin and HIF-1α signaling pathways have been reported to be involved in HCC chemoresistance [37][38][39][40]. In our study, as shown in Fig.…”

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

“…According to our previous researches, 14-3-3η isoform was a novel characteristic neoplastic factor in HCC, inducing the growth/ angiogenesis and MDR properties 15,16 . Moreover, by inhibiting 14-3-3 η, ATO reversed the MDR in HCC cells 11 . However, it is still uninvestigated that whether there are isoforms of 14-3-3 family could function with ATO and enhance the chemotherapeutic efficiency in CCA.…”

“…Meanwhile, ATO is also used to suppressing the progression of many solid tumors, such as breast and liver 8 . We previous revealed that ATO could effectively attenuated the growth/angiogenesis, metastasis, self-renewal, and multidrug resistance via epigenetic modification, regulation of related molecules and chemokines in HCC cells [9][10][11][12] . Nevertheless, the roles of ATO in regulating chemotherapeutic efficiency of CCA, and the potential mechanisms involved in, remains uninvestigated.…”

Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular Carcinoma

“…Then the protein-antibody complexes were incubated with IgG sepharose beads (Beyotime) at 4˚C for another 12 h. After then, the supernatants were removed (positive control) and the beads were washed for three times (residual supernatants, served as a negative control), boiled to remove the beads, centrifugation, and then dissolved the tested substance in water for high-performance liquid chromatography/mass spectrometry (HPLC/MS) analysis, using the Thermo Fisher Q Exactive Plus LC-MS system with the CaA standard as positive control. For the determination of protein ubiquitination, a co-immunoprecipitation assay was performed as described previously [16]. Brie y, HuH7 SR cells were treated, extracted, and the immunoprecipitation complex was prepared as described above.…”