Tau oligomers accumulation sensitizes prostate cancer cells to docetaxel treatment

Stefano Martellucci,Mauro Bologna,Samantha Sabetta,Adriano Angelucci,Vincenzo Mattei,Paola Muzi,Letizia Clementi

doi:10.1007/s00432-021-03598-3

Abstract

PurposeHuman tau is a highly dynamic, multifunctional protein expressed in different isoforms and conformers, known to modulate microtubule turnover. Tau oligomers are considered pathologic forms of the protein able to initiate specific protein accumulation diseases, called tauopathies. In our study, we investigated the potential association between autophagy and tau oligomers accumulation and its role in the response of prostate cancer cells to docetaxel.MethodsWe evaluated in vitro the expression of tau oligomers in prostate cancer cell lines, PC3 and DU145, in presence of autophagy inhibitors and investigated the role of tau oligomers accumulation in resistance to docetaxel treatment.ResultsTau protein was basally expressed in prostate cancer lines as several monomeric and oligomeric forms. The pharmacologic inhibition of autophagy induced in cancer cells the accumulation of tau protein, with a prevalent expression of oligomeric forms. Immunofluorescence analysis of untreated cells revealed that tau was visible mainly in dividing cells where it was localized on the mitotic spindle. Inhibition of autophagy determined an evident upregulation of tau signal in dividing cells and the presence of aberrant monoastral mitotic spindles. The accumulation of tau oligomers was associated with DNA DSB and increased cytotoxic effect by docetaxel.ConclusionsOur data indicate that autophagy could exert a promoting role in cancer growth and during chemotherapy facilitating degradation of tau protein and thus blocking the antimitotic effect of accumulated tau oligomers. Thus, therapeutic strategies aimed at stimulating tau oligomers formation, such as autophagy inhibition, could be an effective adjuvant in cancer therapy.

Highlights

Tau is a heat-stable, highly dynamic, protein known to bind to and stabilize microtubules (Wang and Mandelkow 2016; Kellogg et al 2018)
Starting from this hypothesis we evaluated the expression of tau in prostate cancer cell lines and the role of tau oligomers accumulation in cells treated with docetaxel
bafilomycin A1 (Bfl) and Chl are common and potent inhibitors of cellular autophagy interfering in the formation of autolysosome (Vinod et al 2014; Maclean et al 2008)

Summary

Introduction

Tau is a heat-stable, highly dynamic, protein known to bind to and stabilize microtubules (Wang and Mandelkow 2016; Kellogg et al 2018). Other authors, after observing a higher cancer incidence in families affected by mutated tau and tauopathies, indicated in dysfunctional tau a novel risk factor for cancer (Rossi et al 2018) These initial suggestions recommend further investigation about the possibility that tau expression could represent an advantage for cancer progression in some contexts, and that tau homeostasis could be a therapeutic target. Starting from this hypothesis we evaluated the expression of tau in prostate cancer cell lines and the role of tau oligomers accumulation in cells treated with docetaxel

Materials and methods

Results

Discussion