Plectin in Cancer: From Biomarker to Therapeutic Target.

The cytolinker and scaffolding protein, plectin, has emerged as a potent driver of malignant hallmarks in many human cancers due to its involvement in various cellular activities contributing to tumorigenesis, including cancer cell proliferation, adhesion, migration, invasion, and signal transduction. Evidence shows that beyond plectin's diverse protein interactome, its cancer-specific mislocalization to the cell surface enables its function as a potent oncoprotein. As such, therapeutic targeting of plectin, its protein interactors, and, in particular, cancer-specific plectin (CSP) presents an attractive opportunity to impede carcinogenesis directly. Here, we report on plectin's differential gene and protein expression in cancer, explore its mutational profile, and discuss the current understanding of plectin's and CSP's biological function in cancer. Moreover, we review the landscape of plectin as a prognostic marker, diagnostic biomarker, and target for imaging and therapeutic modalities. We highlight how, beyond their respective biological importance, plectin's common overexpression in cancer and CSP's cancer-specific bioavailability underscore their potential as high-value druggable targets. We discuss how recent evidence of the potent anti-cancer effects of CSP therapeutic targeting opens the door for cell-surface mislocalized proteins as novel therapeutic targets.

Plectin is a novel regulator for apical extrusion of RasV12-transformed cells.

Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine.

Glucosamine-induced reduction of integrin ß4 and plectin complex stimulates migration and proliferation in mouse embryonic stem cells.

We investigated the role of glucosamine (GlcN) on the integrin ß4/plectin complex and its role in the regulation of mouse embryonic stem cell (mESC) migration and proliferation. GlcN significantly decreased integrin ß4 mRNA/protein expression, whereas plectin protein expression did not change. Also, decrease of integrin ß4 expression caused reduction of integrin ß4/plectin complex formation, and then increased cell migration. GlcN increased intracellular calcium influx and protein kinase C (PKC) phosphorylation followed by integrin ß4 serine phosphorylation and reduction of the integrin ß4/plectin complex. GlcN entered into the cell through glucose transporter 1 and then increased O-GlcNAc transferase (OGT) and the level of glycosylation (CTD110.6). Inhibition of OGT (OGT inhibitor; ST045849) increased integrin ß4/plectin complex opposite with decreased cell migration. Moreover, GlcN increased O-GlcNAc-specificity protein 1 (Sp1) and nuclear translocated p-Sp1 stimulated calmodulin (CaM) expression, which combined with plectin. In addition, GlcN increased Akt glycosylation and glycogen synthase kinase-3ß (GSK-3ß) phosphorylation, and then Snail1 glycosylation. Snail small interfering ribonucleic acid (siRNA) reversed the reduction of integrin ß4/plectin complex and dissociation of cell junctions (tight and adherent junction). GlcN increased cell migration, cell cycle regulatory proteins [cyclinD1, cyclin-dependent kinase 4 (CDK4), cyclinE, and CDK2], and the percentage of S phase cells, which were inhibited by a PKC inhibitor, CaM siRNA, or Snail1 siRNA. Additionally, GlcN maintained the undifferentiation status of ESCs. In conclusion, GlcN contributed to migration and proliferation of mESCs through integrin ß4/plectin complex reduction via Ca²âº/PKC, as well as the Sp1/CaM and Akt/GSK-3ß/Snail1 signaling pathway.

Plectin regulates invasiveness of SW480 colon carcinoma cells and is targeted to podosome-like adhesions in an isoform-specific manner.

Co-ordination of cytoskeletal networks and their dynamics is an essential feature of cell migration and cancer cell invasion. Plectin is a large cytolinker protein that influences tissue integrity, organisation of actin and intermediate filaments, and cell migration. Alternatively spliced plectin isoforms are targeted to different subcellular locations. Here, we show that plectin ablation by siRNA impaired migration, invasion and adhesion of SW480 colon carcinoma cells. A previously less well characterised plectin isoform, plectin-1k, co-localised with epithelial integrins, N-WASP, cortactin, and dynamin in podosome-like adhesions in invasive SW480 colon carcinoma cells. Transfection of alternative plectin N-terminal constructs demonstrated that the first exons of isoforms 1k, 1 and 1d can target the actin-binding domain of plectin to podosome-like adhesions. Finally, Plectin-1k N-terminus rescued adhesion site formation in plectin knock-down cells. Thus, plectin participates in actin assembly and invasiveness in carcinoma cells in an isoform-specific manner.

The influence of plectin deficiency on stability of cytokeratin18 in hepatocellular carcinoma.

Intermediate filaments are important in building the cellular architecture. Previously we found cytokeratin18 was modulated in human hepatocellular carcinoma. Plectin is a cross-linking protein that organizes the cytoskeleton into a stable meshwork, which can maintain the uniform size and shape of hepatocytes. Because the cells of hepatocellular carcinoma were morphologically different from the hepatocytes, we speculated that expression of plectin and organization of intermediate filament might play roles in the pleomorphism of hepatocellular carcinoma cells. In this paper, we studied the plectin expression of hepatocellular carcinoma and liver tissues by immunohistochemistry and immunoblot. The results revealed that plectin was deficient and cytokeratin18 was modulated in hepatocellular carcinoma. Furthermore, we knockdown the plectin mRNA in Chang cells, the result revealed the plectin was deficient and the organization of cytokeratin18 was altered. Conclusively, this study offers a hypothesis that plectin deficient might play an important role in the tumorigenesis of hepatocellular carcinoma.