No abstract

Diverse essential cellular behaviors are determined by extracellular physical cues that are detected by highly orchestrated subcellular interactions with the extracellular microenvironment. To maintain the reciprocity of cellular responses and mechanical properties of the extracellular matrix, cells utilize a variety of signaling pathways that transduce biophysical stimuli to biochemical reactions. Recent advances in the micromanipulation of individual cells have shown that cellular responses to distinct physical and chemical features of the material are fundamental determinants of cellular mechanosensation and mechanotransduction. In the process of outside-in signal transduction, transmembrane protein integrins facilitate the formation of focal adhesion protein clusters that are connected to the cytoskeletal architecture and anchor the cell to the substrate. The linkers of nucleoskeleton and cytoskeleton molecular complexes, collectively termed LINC, are critical signal transducers that relay biophysical signals between the extranuclear cytoplasmic region and intranuclear nucleoplasmic region. Mechanical signals that involve cytoskeletal remodeling ultimately propagate into the nuclear envelope comprising the nuclear lamina in assistance with various nuclear membrane proteins, where nuclear mechanics play a key role in the subsequent alteration of gene expression and epigenetic modification. These intracellular mechanical signaling cues adjust cellular behaviors directly associated with mechanohomeostasis. Diverse strategies to modulate cell-material interfaces, including alteration of surface rigidity, confinement of cell adhesive region, and changes in surface topology, have been proposed to identify cellular signal transduction at the cellular and subcellular levels. In this review, we will discuss how a diversity of alterations in the physical properties of materials induce distinct cellular responses such as adhesion, migration, proliferation, differentiation, and chromosomal organization. Furthermore, the pathological relevance of misregulated cellular mechanosensation and mechanotransduction in the progression of devastating human diseases, including cardiovascular diseases, cancer, and aging, will be extensively reviewed. Understanding cellular responses to various extracellular forces is expected to provide new insights into how cellular mechanoadaptation is modulated by manipulating the mechanics of extracellular matrix and the application of these materials in clinical aspects.

Acquisition of acquired chemoresistance during treatment cycles in urothelial carcinoma of the bladder (UCB) is the major cause of death through enhancing the risk of cancer progression and metastasis. Elevated glucose flux through the abnormal upregulation of O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) controls key signaling and metabolic pathways regulating diverse cancer cell phenotypes. This study showed that OGT expression levels in two human UCB cell models with acquired resistance to gemcitabine and paclitaxel were significantly upregulated compared with those in parental cells. Reducing hyper-O-GlcNAcylation by OGT knockdown (KD) markedly facilitated chemosensitivity to the corresponding chemotherapeutics in both cells, and combination treatment with OGT-KD showed more severe growth defects in chemoresistant sublines. We subsequently verified the suppressive effects of OGT-KD monotherapy on cell migration/invasion in vitro and xenograft tumor growth in vivo in chemoresistant UCB cells. Transcriptome analysis of these cells revealed 97 upregulated genes, which were enriched in multiple oncogenic pathways. Our final choice of suspected OGT glycosylation substrate was VCAN, S1PR3, PDGFRB, and PRKCG, the knockdown of which induced cell growth defects. These findings demonstrate the vital role of dysregulated OGT activity and hyper-O-GlcNAcylation in modulating treatment failure and tumor aggression in chemoresistant UCB.