Genistein is an important chemopreventive agent against atherosclerosis and cancer. However, whether genistein is effective in the treatment of lung cancer, and its underlying mechanism, remains to be determined. The present study demonstrated that genistein treatment of A549 lung cancer cells decreased viability in a dose‑ and time‑dependent manner, and induced apoptosis. Additionally, A549 cells exhibited significantly increased reactive oxygen species formation and cytochrome‑c leakage, and activated caspase‑3, B‑cell lymphoma 2‑associated X protein and apoptosis inducing factor expression levels, which are involved in the mitochondrial apoptosis pathway. Furthermore, the phosphatidylinositol‑4,5‑biphosphate 3‑kinase (PI3K)/protein kinase B (AKT)/hypoxia‑inducible factor‑1α (HIF‑1α) and nuclear factor‑κB (NF‑κB)/cyclooxygenase‑2 (COX‑2) signaling pathways were significantly downregulated by genistein treatment. In conclusion, reduced proliferation and increased apoptosis in A549 lung cancer cells was associated with inhibition of the PI3K/AKT/HIF‑1α/ and NF‑κB/COX‑2 signaling pathways, which implicates genistein as a potential chemotherapeutic agent for the treatment of lung cancer.
We investigated whether MAPK-interacting kinase (Mnk) inhibition sensitizes anaplastic thyroid cancer (ATC) cellular response to chemotherapy.In vitro and in vivo methods were used to examine the combinatory effects of cisplatin with Mnk inhibition and its underlying mechanism.Mnk inhibition by pharmacological or genetic approaches inhibits proliferation and induces apoptosis of ATC cells and enhances the effects of cisplatin in in vitro and in vivo. Mechanistically, cisplatin increases eIF4E phosphorylation in a dose- and time-dependent manner in ATC cells. Mnk inhibitors sensitize the efficacy of cisplatin by inhibiting cisplatin-induced eIF4E phosphorylation.Targeting Mnk-eIF4E pathway provides a therapeutic strategy by sensitizing ATC response to chemotherapeutic drug.
Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 was increased in HCC, promoting the proliferation of HCC cells. RNAseq data indicated that the absence of ZMAT2 induced skipping exon of mRNA, while RIPseq data further revealed the mRNA binding motifs of ZMAT2. A comprehensive analysis of RNAseq and RIPseq data indicateed that ZMAT2 played a crucial role in the maturation process of TRIM28 mRNA. Knocking down of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Our data revealed that ZMAT2 could regulate TRIM28 to reduce the accumulation of ROS in HCC cells, thereby promoting their proliferation. Our research also discovered that ZMAT2 was capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within HCC cells. Additionally, it was found that ZMAT2 was able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, this study is the first to reveal that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The increased expression of ZMAT2 in HCC leads to upregulated TRIM28 expression and reduced ROS accumulation, ultimately accelerating the proliferation of HCC cells.
Abstract Mitochondrial structure is dynamically regulated by fusion and fission events that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial dynamics in metastasis, the major cause of cancer death. In the present study, we found that mitochondria were more fragmented in metastatic breast cancer cells that express higher levels of mitochondrial fission protein dynamin-related protein 1 (Drp1) and less mitochondrial fusion protein 1 (Mfn1). Silence of Drp1 or overexpression of Mfn1 resulted in mitochondria elongation and significantly suppressed metastatic abilities of breast cancer cells. In contrast, silence of Mfn proteins led to mitochondrial fragmentation and enhanced metastatic abilities of breast cancer cells. Interestingly, these manipulations of mitochondrial dynamics had no significant effects on overall mitochondrial bioenergetics but altered the subcellular distribution of mitochondria in breast cancer cells. Silence of Drp1 or overexpression of Mfn1 inhibited lamellipodia formation, a key step for cancer metastasis, and suppressed chemoattractant-induced recruitment of mitochondria to lamellipodial regions. Conversely, silence of Mfn proteins caused accumulation of more mitochondria in lamollipodia regions with higher mitochondrial membrane potential, an indication of higher ATP synthesis. Treatment with the ATP uncoupling agent m-chlorophenylhydrazone (CCCP) or mitochondrial ATP synthesis inhibitor oligomycin A caused disappearance of lamellipodia and decreased breast cancer cell migration and invasion. Together, our findings show a new mechanism for regulation of cancer cell migration and invasion by mitochondrial dynamics. Thus targeting mitochondrial dynamics may provide a novel strategy for suppressing breast cancer metastasis. This work was supported by the National Institutes of Health (CA125661), State of Nebraska Research Fund (Grant LB595), the National Natural Science Foundation of China (31100973) and the National Basic Research Program (2010CB833701, 2012CB934003). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 467. doi:1538-7445.AM2012-467
Abstract Cytoskeletal rearrangement is a critical component to hematopoietic stem cell development and differentiation into mature leukocyte populations. A number of chemokines and biolipids have been shown to regulate these events via binding to G protein coupled receptors. Many of these receptors couple to the Ga12/13 family of G proteins to regulate actin reorganization via the RhoA small GTPase. The Rho-kinases, Rock1 and Rock2, are activated downstream of RhoA to induce cytoskeletal changes that regulate numerous cellular processes, including contraction, polarity, proliferation, motility, adhesion and viability. A role for RhoA in regulating hematopoiesis and subsequent leukocyte development has been established using genetic studies. However, a similar role for the Rock1 and Rock2 has not been demonstrated. As global deletion of either kinase causes embryonic lethality, we used conditional gene targeting to ablate either the Rock1 or Rock2 allele in adult mice. Rock1flox/flox or Rock2flox/flox mice were crossed to the Rosa26-Cre ERT2 line to globally delete the floxed alleles with tamoxifen. In contrast to deletion of RhoA, conditional deletion of either Rock1 or Rock2 was well-tolerated, with no aberrant effects on hematopoiesis. These results suggest functional redundancy between Rock1 and Rock2 in regulating RhoA activity in hematopoiesis. However, we observed a significant decrease in marginal zone B cell number and frequency in the spleen of mice lacking Rock1. We also observed a follicular B cell defect in the spleen of mice lacking Rock2. These results are consistent with the known roles of GPCRs in B cell migration/positioning, and suggest there are isoform specific functions of these kinases.
Ferroptosis is a form of programmed cell death that is distinct from apoptosis. The mechanism involves redox‑active metallic iron and is characterized by an abnormal increase in iron‑dependent lipid reactive oxygen species, which results in high levels of membrane lipid peroxides. The relationship between ferroptosis and gynaecological tumours is complex. Ferroptosis can regulate tumour proliferation, metastasis and chemotherapy resistance, and targeting ferroptosis is a promising antitumour approach. Ferroptosis interacts with mechanisms related to tumorigenesis and development, such as macrophage polarization, the neutrophil trap network, mitochondrial autophagy and cuproptosis. The present review examines recent information on the interaction between the molecular mechanism of ferroptosis and other tumour‑related mechanisms, as well as the involvement of ferroptosis in gynaecological tumours, to identify implications for gynaecological cancer therapy.
Abstract Highly specific and potent inhibitors of dihydroorotate dehydrogenase (DHODH), an essential enzyme of the de novo pyrimidine ribonucleotide synthesis pathway, are in clinical trials for autoimmune diseases, viral infections and cancer. However, because DHODH inhibitors (DHODHi) are immunosuppressants they may reduce the anticancer activity of the immune system. Therefore, there may be a need to improve the therapeutic index of DHODHi in cancer patients. The aim of this study was to find strategies to protect activated T cells from DHODHi and to identify cancer types hypersensitive to these inhibitors. First, we observed that like uridine supplementation, adding cytidine to the culture medium protects T cells from DHODH blockage. Next, we identified tumor types with altered expression of pyrimidine ribonucleotide synthesis enzymes. In this regard, we detected that the expression of cytidine deaminase (CDA), which converts cytidine into uridine, is low in an important proportion of cancer cell lines and consistently low in neuroblastoma samples and in cell lines from neuroblastoma and small cell lung carcinoma. This suggested that in the presence of a DHODHi, an excess of cytidine would be deleterious for low CDA expressing cancer cell lines. We show that this was the case (as could be seen almost immediately after treatment) when cells were cultured with fetal bovine serum but, was significantly less evident when cultures contained human serum. One interesting feature of CDA is that aside from acting intracellularly, it is also present in human plasma/serum. Altogether, experiments using recombinant CDA, human serum, pharmacologic inhibition of CDA and T cell/cancer cell co-cultures suggest that the therapeutic index of DHODHi could be improved by selecting patients with low-CDA expressing cancers in combination with strategies to increase cytidine or the cytidine/uridine ratio in the extracellular environment. Collectively, this proof-of-principle study warrants the discovery of agents to deplete extracellular CDA.
Cancer-associated fibroblast (CAF) is among the most important tumor-host microenvironment components by affecting tumor progression. This study explored the role of miR-224 in CAF-induced non-small cell lung cancer (NSCLC).
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