Background: Increasing evidence suggests that glutathione peroxidase 2 (GPX2) plays important roles in the tumorigenesis and progression of various human cancers, such as colorectal carcinomas and lung adenocarcinomas. However, the role of GPX2 in cervical cancer is unclear. In this study, we identified the role of GPX2 in cervical cancer tissues and cell lines. Materials and methods: The basal mRNA and protein expression of GPX2 in cervical cancer cells and a series of key molecules in the epithelial to mesenchymal transition (EMT) and WNT/β-catenin pathways were examined via real time fluorescence quantitative PCR (qRT-PCR) and Western blot assays. The biological phenotype of the cervical cancer cell lines was detected by the cloning formation and transwell assays, and intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. Finally, the GPX2 expression level in 100 clinical cervical tissues was examined by immunohistochemistry. Results: We found that GPX2 was highly expressed in cervical cancer tissues compared to normal individuals and promoted the proliferation and metastasis of cervical cancer cells, and this promotion correlated with the activation of EMT and WNT/β-catenin signaling in vitro. GPX2 was determined to reduce apoptotic damage by reducing hydroperoxides. According to the characteristics and verification of GPX2, this series of phenotypes is clearly related to oxidative stress in cells. Furthermore, we verified that GPX2 was highly expressed in cervical cancer tissues and promoted the metastasis of cervical cancer. Conclusion: In summary, we found that GPX2 was highly expressed in cervical cancer cells and promoted the proliferation and metastasis of cervical cancer by affecting oxidative stress. Our study provides a new target for the clinical treatment of cervical cancer.
Trametinib is a MEK1/2 inhibitor and exerts anticancer activity against a variety of cancers. However, the effect of Trametinib on colorectal cancer (CRC) is not well understood. In the current study, our results demonstrate the ability of sub‐toxic doses of Trametinib to enhance TRAIL‐mediated apoptosis in CRC cells. Our findings also indicate that Trametinib and TRAIL activate caspase‐dependent apoptosis in CRC cells. Moreover, Mcl‐1 overexpression can reduce apoptosis in CRC cells treated with Trametinib with or without TRAIL. We further demonstrate that Trametinib degrades Mcl‐1 through the proteasome pathway. In addition, GSK‐3β phosphorylates Mcl‐1 at S159 and promotes Mcl‐1 degradation. The E3 ligase FBW7, known to polyubiquitinate Mcl‐1, is involved in Trametinib‐induced Mcl‐1 degradation. Taken together, these results provide the first evidence that Trametinib enhances TRAIL‐mediated apoptosis through FBW7‐dependent Mcl‐1 ubiquitination and degradation.
Poly(ADP-ribose) polymerase (PARP) inhibitors have little effect on homologous recombination repair (HRR)-proficient tumor types, such as cervical cancer. In addition to catalytic activity, the PARP inhibitor, BMN673, traps PARP1 on damaged DNA and induces cytotoxic effects. The aim of the present study was to evaluate the therapeutic effect of PI3K inhibitors and BMN673 on cervical cancer cells. The Chou-Talalay method was used to assess the synergistic effect of drug combinations on cervical cancer cells. The effect of PI3K inhibitors and BMN673 on cell growth and survival were also assessed via a Cell Counting Kit-8 assay and three-dimensional sphere culture. Cell migration and invasion were assessed via Transwell migration and Matrigel invasion assays, respectively. In addition, DNA damage and HRR competency were assessed via immunofluorescent staining analysis of γH2AX and RAD51 foci, and tail moment in a comet assay. PARP1 binding in chromatin was assessed via a cellular trapping assay. Ex vivo cultured sections of patient-derived cervical tumors were subjected to drug exposure followed by histological and immunohistochemical analyses. The results revealed that the PI3K p110α inhibitor BYL719 and the PARP inhibitor BMN673 synergized to inhibit cervical cancer cell proliferation, migration and invasion in vitro and ex vivo. However, the pan-PI3K inhibitor BKM120 did not produce the aforementioned effects. Additionally, cervical cancer cells exhibiting aberrant PI3K activation were more responsive to the combined inhibition of PI3K p110α and PARP. Mechanistically, BYL719 cooperated with BMN673 to increase PARP1 trapping on chromatin, induce severe DNA damage and exert cytotoxic effects. The combined use of BMN673 and BYL719 may serve as a promising therapeutic strategy for patients with cervical cancer exhibiting aberrant PI3K activation.
Background: Bladder cancer is the ninth most common cancer worldwide and has high morbidity and mortality. We aimed to search for potential serum peptide biomarkers and establish a diagnostic model for early bladder cancer. Methods: A total of 67 bladder cancer patients and 64 healthy volunteers were randomly divided into a training set and testing set 1. There were 30 hematuria patients used as testing set 2. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based on weak cation exchange magnetic beads was used to obtain and analyze the serum peptide profiles between bladder cancer patients and healthy volunteers in the training set. Serum peptide diagnostic model through a k-nearest neighbor algorithm, was established and validated, and significantly differentially expressed protein biomarkers were ultimately identified. Results: We constructed a diagnostic model containing five peptides (m/z 1954.9, m/z 2081.0, m/z 3938.3, m/z 3946.5, and m/z 4268.8). In the training set, the area under the curve (AUC) value of the five-peptide model was 0.923, and the sensitivity and specificity was 93.75% and 96.77%, respectively. In testing set 1, the sensitivity and specificity was 91.43% and 90.91%, respectively, and the specificity of testing set 2 was 73.33%. For early-stage bladder cancer, the sensitivity and specificity was 92.31% and 93.75%, respectively; the sensitivity of early low-grade bladder cancer was 90.00%; and the AUC value was 0.944. Conclusion: The five-peptide diagnostic model established in this study had high sensitivity and specificity, especially in the diagnosis of early bladder cancer, and could differentiate between healthy volunteers and hematuria patients.
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