alpha-Tubulin detyrosination links the suppression of MCAK activity with taxol cytotoxicity

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Lopes, D (Author) Other; Seabra, AL (Author) Other; Orr, B (Author) Other; Helder Maiato (Author) FMUP

Journal

Title: Journal of Cell Biology

Vol. 222

ISSN: 0021-9525

Publisher: Rockefeller University Press

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: P-00X-M3B

DOI: 10.1083/jcb.202205092

Abstract (EN): Lopes et al. perform a pilot dissection of the cancer tubulin code in the NCI-60 cancer cell panel that identifies high alpha-tubulin acetylation as a biomarker of taxol response and unveils a mechanistic link between alpha-tubulin detyrosination and the suppression of MCAK activity in taxol-induced cytotoxicity. alpha/beta-Tubulin posttranslational modifications (PTMs) generate microtubule diversity, but whether they account for cancer cell resistance to microtubule-targeting drugs remains unknown. Here, we performed a pilot dissection of the cancer tubulin code using the NCI-60 cancer cell panel. We found that acetylated, detyrosinated, and 2-alpha-tubulin that typically accumulate on stable microtubules were uncoupled in many cancer cells. Acetylated alpha-tubulin did not affect microtubule dynamics, whereas its levels correlated with, but were not required for, taxol-induced cytotoxicity. In contrast, experimental increase of alpha-tubulin detyrosination, and/or depletion of the detyrosination-sensitive microtubule-depolymerizing enzyme MCAK, enhanced taxol-induced cytotoxicity by promoting cell death in mitosis and the subsequent interphase, without causing a cumulative effect. Interestingly, only increased detyrosinated alpha-tubulin aggravated taxol-induced spindle multipolarity. Overall, we identified high alpha-tubulin acetylation as a potential biomarker for cancer cell response to taxol and uncovered a mechanistic link between alpha-tubulin detyrosination and the suppression of MCAK activity in taxol-induced cytotoxicity, likely by promoting chromosome missegregation, regardless of spindle defects.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 25