Accumulation of Phosphorylated Tau Protein Interferes with Mitosis in Cancer Cells

Introduction. Tauopathies are neurodegenerative diseases characterized by aggregates of hyperphosphorylated tau. Previous studies have identified many disease-related phosphorylation sites on tau and it is widely accepted that tau hyperphosphorylation blocks tau ability to bind and stabilize microtubules. Formation of oligomeric tau has been described as the initial event in tauopathies and it represents a potent stressor in neuronal cells. However, mechanisms underlying tau oligomerization and its role in cell homeostasis are largely unknown. Methods. In our study we investigated the role of tau accumulation in glioblastoma cells. In particular, we evaluated in vitro, the role of tau hyperphosphorylation, analyzing morphological and molecular consequences during cell cycle progression. Results. Tau protein was expressed in different glioblastoma cell lines and western blot analysis showed the presence of several phosphorylated forms. The chemical inhibition of phosphatases induced in cancer cells the accumulation of tau protein, with an increased expression of both phosphorylated and high molecular weight oligomeric forms. In parallel, we observed an increment in the number of cells in G2/M phase of cell cycle with the formation of aberrant mitotic spindle and aneuploidy. As demonstrated by immunofluorescence, hyperphosphorylation determined an evident upregulation of tau expression in dividing cells with a diffuse protein localization in cytoplasm rather than on mitotic spindle. Interestingly, the pharmacologic inhibition of autophagy by treatment with chloroquine, synergized with tau accumulation and increase its cytotoxic effect. In addition, we individuated CDK5 as major contributor to tau hyperphosphorylation and aberrant mitosis. Conclusions. Our data indicate that aberrant control of tau phosphorylation is important in allowing cancer progression and that the accumulation of hyperphosphorylated tau has an inhibitory role on mitosis. Thus, the understanding of molecular mechanisms underlying the homeostatic control of tau protein could suggest new therapeutic targets also in cancer