Resistance to paclitaxel induces glycophenotype changes and mesenchymal-to-epithelial transition activation in the human prostate cancer cell line PC-3

Abstract

The development of the multidrug resistance phenotype is one of the major challenges faced in the treatment of cancer. The multidrug resistance phenotype is characterized by cross-resistance to drugs with different chemical structures and mechanisms of action. In this work, we hypothesized that the acquisition of resistance in cancer is accompanied by activation of the epithelial-to-mesenchymal transition process, where the tumor cell acquires a more mobile and invasive phenotype; a fundamental step in tumor progression and in promoting the invasion of other organs and tissues. In addition, it is known that atypical glycosylations are characteristic of tumor cells, being used as biomarkers. We believe that the acquisition of the multidrug resistance phenotype and the activation of epithelial-to-mesenchymal transition provoke alterations in the cell glycophenotype, which can be used as glycomarkers for chemoresistance and epithelial-to-mesenchymal transition processes. Herein, we induced the multidrug resistance phenotype in the PC-3 human prostate adenocarcinoma line through the continuous treatment with the drug paclitaxel. Our results showed that the induced cell multidrug resistance phenotype (1) acquired a mixed profile between epithelial and mesenchymal phenotypes and (2) modified the glycophenotype, showing an increase in the level of sialylation and in the number of branched glycans. Both mechanisms are described as indicators of poor prognosis.

Expression of GnT-III decreases chemoresistance via negatively regulating P-glycoprotein expression: Involvement of the TNFR2-NF-κB signaling pathway

“…Thus, GnT-III is generally regarded as a key glycosyltransferase in N -glycan biosynthetic pathways ( 37 ). Previous studies have shown that the expression levels of GnT-III are decreased in several drug-resistant cell lines ( 38 , 39 ). Moreover, a knockdown of GnT-III has increased the resistance to 5-fluorouracil in human hepatocarcinoma cells ( 31 ).…”

Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention

“…In respect to PTX resistance of prostate cancer cells, polymeric nanoparticles have been applied for targeted delivery of PTX [294]. Furthermore, activation of molecular mechanisms such as EMT stimulates PTX resistance [295]. LncRNA CCAT1 undergoes overexpression in PTX resistant-prostate cancer cells and prevents apoptosis.…”

Glycobiology of Cancer: Sugar Drives the Show

“…When it comes to N-linked glycans, however, there is more to the story. Many groups show an abundance of long, branched, and hypersialylated structures [30][31][32][33][34][35], while others report high mannose structures [36,37] or even both [38]. One particular study points to high mannose structures being prevalent in the primary tumor, while branched sialylated epitopes are found in metastatic foci [39].…”

“…Recent studies have demonstrated that altered glycosylation of proteins that make up the glycocalyx may be recognized by immune cells, leading to induction of inhibitory immune processes, which subsequently drive tumor growth and metastasis [41]. Several studies developed by our research group demonstrated that Oand N-linked unusual glycan structures govern phenomena associated to the epithelial-mesenchymal transition (EMT) process, as well as the acquisition/maintenance of the multidrug resistance (MDR) phenotype [12,34,35,[42][43][44][45][46][47][48][49][50]. MDR phenotype and the acquisition of metastatic properties by cancer cells are known as the main obstacles to the treatment of different types of cancer [51].…”

“…In recent works, we have demonstrated for the first time that alterations in glycosylation in tumor cells chronically exposed to chemotherapeutic agents, are able to connect both MDR phenotype and EMT process, since in addition to presenting changes in the expression and/or activity of efflux pumps belonging to the ABC superfamily (ABCB1, ABCC1 and ABCG2) [55,56], the chemoresistant human cancer cell lines also showed increased cell motility, as well as altered expression of epithelial-mesenchymal markers, when compared with their normal counterparts [34,35]. These findings confirm the idea that both accretion of MDR phenotype and the activation of EMT process, which have been considered indispensable for invasion and metastasis [57][58][59], are deeply linked with unusual glycan structures expressed by transformed cells.…”