Tau oligomers accumulation sensitizes prostate cancer cells to docetaxel treatment

Abstract

Purpose Human 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. Methods We 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. Results Tau 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. Conclusions Our 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.

Tau Isoforms: Gaining Insight into MAPT Alternative Splicing

“…For instance, in ovarian cancer, the down-regulation of Tau affected the viability of the high Tau-expressing TOV112V cell line while did not affect the low-Tau-expressing OVCAR cell line, suggesting a possible link with the microtubule composition and the level of Tau expression [ 91 , 106 , 108 ]. Moreover, some authors proposed a direct function of Tau in stabilizing DNA and/or mitotic spindle assembly, conferring a selective advantage for cancer cell growth [ 99 , 109 ].…”

Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis

“…For instance, in ovarian cancer, the down-regulation of Tau affected the viability of the high Tau-expressing TOV112V cell line while did not affect the low-Tau expressing OVCAR cell line (Yamauchi et al, 2017). It has also been proposed as a direct function of Tau in stabilizing DNA and/or mitotic spindle assembly, conferring a selective advantage for cancer cell growth [ 45 , 46 ].…”

Tau Protein as Therapeutic Target for Cancer? Focus on Glioblastoma

“…One hypothesis may imply MTA-mediated activation of different cell death pathways such as autophagy, a mechanism in which the quantity of Tau could promote. Indeed, the potential association between autophagy inhibition and Tau has been recently investigated in prostate cancer cells where the presence of aberrant monoastral mitotic spindles has been evidenced to correlate both with the accumulation of Tau oligomers and with a recovered cytotoxic effect of docetaxel [ 95 ]. Interestingly, the authors suggest that cancer could maintain a high Tau protein turnover to avoid the formation of toxic oligomers, mainly during mitosis, through defective autophagy.…”

“…Likewise, in the regulation of Tau post-translational modifications, the lack of knowledge on the Tau aggregation state in GBM makes it hard to assess the potential efficiency of aggregation inhibitors for treatment. In contrary to neurons, Tau oligomers accumulation in cells was not toxic such as in prostate cancer but they sensitized them to radiotherapy [ 95 ]. Alternatively, we can also propose that modulators of Tau aggregation may sequester monomeric Tau making it unavailable for other interactions; therefore, this approach might show some benefit in GBM therapy.…”