ABSTRACT
Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft
ABSTRACT
Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
ABSTRACT
Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/ mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both and . Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.
ABSTRACT
ErbB-3 binding protein 1 (Ebp1) is a host protein which binds ErbB-3 receptor to induce signalling events for cell growthregulation. In addition, Ebp1 also interacts with ribonucleoprotein complexes. In recent times, Ebp1 was found to play anantagonistic role in viral infections caused by Influenza and Rinderpest viruses. In our present work we have tried tounderstand the role of Ebp1 in Chandipura virus (CHPV) infection. We have observed an induction in Ebp1 expressionupon CHPV infection similar to other viruses. However, unlike other viruses an overexpressed Ebp1 only reduces viralprotein expression, but does not affect its progeny formation. Additionally, this effect is being carried out in an indirectmanner, as there is no interaction between Ebp1 and viral proteins. This is despite Ebp1’s presence in viral inclusion bodies.
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Purpose To study the expression of eIF-4E and p-4EBP-1 and its clinical significance in the gastric carcinoma.Methods Expression of eIF-4E and p-4EBP-1 was detected in tissue array including 168 cases of gastric carcinoma and 52 cases of peri-cancer tissues by immunohistochemical SP method.Results The positive expression of eIF-4E and p-4EBP-1 in the gastric carcinoma was significantly higher than that of peri-cancer tissues (P =0.001,P =0.000).There was significantly higher expression of eIF-4E and p-4EBP-1 with lymph node metastases than without lymph node metastases in the gastric carcinoma (P =0.025,P =0.001).Also,there was significantly higher expression of eIF-4E and p-4EBP-1 with clinical stages Ⅲ + Ⅳ than that of stages Ⅰ + Ⅱ (P =0.001,P=0.049).In addition,there was a significantly positive correlation between the expression of eIF-4E and p-4EBP-1 in the gastric carcinoma (r =0.432,P ＜ 0.01).The overall survival rates for patients with negative expression of eIF-4E protein was higher than that with positive expression (P =0.012).Conclusion The abnormal co-expression of eIF-4E and p-4EBP-1 may be related to the tumorgenesis,development,metastasis and invasion of gastric carcinoma,and eIF-4E and p-4EBP-1 may act as the new molecular targets for the therapy and diagnosis of gastric carcinoma.
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This work summarizes the research development and molecular mechanism of Ebp1, a member of the proliferation-associated 2G4 family, in tumor proliferation and invasion. This research serves as a basis and support for further research on the mechanism of tumor proliferation and invasion. The low expression of Ebp1 in various cancers promotes tumor proliferation and invasion. Ebp1 inhibits E2F1, cyclin D1, and cyclin E transcription by interacting with Rb, human histone deacetylase 2, and the transcriptional repressor Sin3A. This inhibition triggers cell cycle arrest and suppresses cell proliferation. Ebp1 also influences cancer invasion and migration. However, the underlying mechanisms remain unknown and require further exploration.
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Long-term synaptic plasticity requires addition of new proteins at the synaptic site. The local protein synthesis at subsynaptic sites confers advantageous mechanisms that would regulate the protein composition in local domains on a moment-by-moment basis. However, our information on the identities of 'dendritic' mRNAs is very limited. In this study we investigated the expression of the protein and mRNA for eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) in cultured rat hippocampal neurons. Immunocytochemistry (ICC) showed that 4EBP1 protein is highly localized to the nucleus. In dendrites most 4EBP1 punctae were not colocalized with those of eIF4E. In situ hybridization (ISH) and Fluorescence ISH (FISH) revealed that 4EBP1 mRNA was present in dendrites. The FISH signals formed clusters along dendrites that colocalized with ICC signals for Staufen, a marker for RNA granules. The neuronal activation by KCl (60 mM, 10 min) significantly increased the density of 4EBP1 FISH signals in the nucleus after 2 hr, and both in the nucleus and dendrites after 6 hr. Our results indicate that 4EBP1 and its mRNA are present in dendrites, and the mRNA is upregulated and transported to dendritic domains in RNA granules upon neuronal activation.