Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors

Senichkin, V.V.; Pervushin, N.V.; Zamaraev, A.V.; Sazonova, E.V.; Zuev, A.P.; Streletskaia, A.Y.; Prikazchikova, T.A.; Zatsepin, T.S.; Kovaleva, O.V.; Tchevkina, E.M.; Zhivotovsky, B.; Kopeina, G.S.

Статья опубликована в высокорейтинговом журнале

Информация о цитировании статьи получена из Web of Science, Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 4 марта 2022 г.

Авторы: Senichkin V.V., Pervushin N.V., Zamaraev A.V., Sazonova E.V., Zuev A.P., Streletskaia A.Y., Prikazchikova T.A., Zatsepin T.S., Kovaleva O.V., Tchevkina E.M., Zhivotovsky B., Kopeina G.S.
Журнал: Cancers
Том: 14
Номер: 1
Год издания: 2022
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Номер статьи: 181
DOI: 10.3390/cancers14010181
Аннотация: BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targetingthe Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigationof their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477and S63845, and found their different efficacies in on-target doses, despite the fact that both agentsinteracted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependentmechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance toMcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissuesfrom patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increasedBak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrateddramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL andMcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins.Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced celldeath, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak andBcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.
Добавил в систему: Первушин Николай Викторович

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