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

Autor:	Lopes D; Chromosome Instability & Dynamics Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Seabra AL; Chromosome Instability & Dynamics Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Orr B; Chromosome Instability & Dynamics Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Maiato H; Chromosome Instability & Dynamics Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.; Cell Division Group, Department of Biomedicine, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2023 Feb 06; Vol. 222 (2). Date of Electronic Publication: 2022 Dec 02.
DOI:	10.1083/jcb.202205092
Abstrakt:	α/β-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-α-tubulin that typically accumulate on stable microtubules were uncoupled in many cancer cells. Acetylated α-tubulin did not affect microtubule dynamics, whereas its levels correlated with, but were not required for, taxol-induced cytotoxicity. In contrast, experimental increase of α-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 α-tubulin aggravated taxol-induced spindle multipolarity. Overall, we identified high α-tubulin acetylation as a potential biomarker for cancer cell response to taxol and uncovered a mechanistic link between α-tubulin detyrosination and the suppression of MCAK activity in taxol-induced cytotoxicity, likely by promoting chromosome missegregation, regardless of spindle defects. (© 2022 Lopes et al.)
Databáze:	MEDLINE
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