ABSTRACT
Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1.
Subject(s)
Cancer-Associated Fibroblasts , Kruppel-Like Transcription Factors , PTEN Phosphohydrolase , Prostatic Neoplasms , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/genetics , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Humans , Acetylation , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Kruppel-Like Transcription Factors/metabolism , Kruppel-Like Transcription Factors/genetics , Animals , Mice , Cellular Reprogramming , Cell Line, TumorABSTRACT
Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscoreaceae, has lipid-lowering and broad anticancer properties. However, the efficacy of MPD in treating prostate cancer remains unexplored. Therefore, the present study aimed to evaluate the anticancer activity and action mechanism of MPD in prostate cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, and flow cytometer assays revealed that MPD suppressed proliferation, migration, cell cycle, and invasion and induced apoptosis of DU145 cells. Mechanistically, MPD decreased cholesterol concentration in the cholesterol oxidase, peroxidase and 4-aminoantipyrine phenol (COD-PAP) assay, disrupting the lipid rafts as detected using immunofluorescence and immunoblot analyses after sucrose density gradient centrifugation. Further, it reduced the associated mitogen-activated protein kinase (MAPK) signaling pathway protein P-extracellular regulated protein kinase (ERK), detected using immunoblot analysis. Forkhead box O (FOXO)1, a tumor suppressor and critical factor controlling cholesterol metabolism, was predicted to be a direct target of MPD and induced by MPD. Notably, in vivo studies demonstrated that MPD significantly reduced tumor size, suppressed cholesterol concentration and the MAPK signaling pathway, and induced FOXO1 expression and apoptosis in tumor tissue in a subcutaneous mouse model. These results suggest that MPD displays anti-prostate cancer activity by inducing FOXO1 protein, reducing cholesterol concentration, and disrupting lipid rafts. Consequently, the reduced MAPK signaling pathway suppresses proliferation, migration, invasion, and cell cycle and induces apoptosis of prostate cancer cells.
Subject(s)
Prostatic Neoplasms , Saponins , Humans , Male , Animals , Mice , Mitogen-Activated Protein Kinases/metabolism , Cell Line, Tumor , Signal Transduction , Saponins/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Cell Proliferation , Apoptosis , Cell Movement , MAP Kinase Signaling System , Forkhead Box Protein O1/metabolismABSTRACT
Compatibility, a critical issue between sensing material and host structure, significantly influences the detecting performance (e.g., sensitive, signal-to-noise ratio) of the embedded sensor. To address this issue in concrete-based infrastructural health monitoring, cement-based piezoelectric composites (piezoelectric ceramic particles as a function phase and cementitious materials as a matrix) have attracted continuous attention in the past two decades, dramatically exhibiting superior durability, sensitivity, and compatibility. This review paper performs a synthetical overview of recent advances in theoretical analysis, characterization and simulation, materials selection, the fabrication process, and application of the cement-based piezoelectric composites. The critical issues of each part are also presented. The influencing factors of the materials and fabrication process on the final performance of composites are further discussed. Meanwhile, the application of the composite as a sensing element for various monitoring techniques is summarized. Further study on the experiment and simulation, materials, fabrication technique, and application are also pointed out purposefully.
ABSTRACT
A novel microcapsule-based self-immunity system for reinforced concrete is proposed. Its feasibility for hindering the corrosion of steel rebar by means of lifting the threshold value of [Cl(-)]/[OH(-)] is discussed. Precisely controlled release behavior enables corrosion protection in the case of depassivation. The release process is characterized over a designated range of pH values, and its release characteristics of the microcapsules, triggered by decreasing pH value, are captured by observing that the core crystals are released when exposed to a signal (stimulus). The aim of corrosion protection of steel bar is achieved through the constantly-stabilized passive film, and its stability is promoted using continuous calcium hydroxide released from the microcapsule, restoring alkaline conditions. The test results exhibited that the release process of the microcapsules is a function of time. Moreover, the release rate of core materials could interact with environmental pH value, in which the release rate is found to increase remarkably with decreasing pH value, but is inhibited by high pH levels.
