Next Article in Journal
Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis
Previous Article in Journal
Robotic-Assisted vs. Standard Laparoscopic Surgery for Rectal Cancer Resection: A Systematic Review and Meta-Analysis of 19,731 Patients
Previous Article in Special Issue
Targeted Cancer Therapy Using Compounds Activated by Light
 
 
Article

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

1
Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia
2
Skolkovo Institute of Science and Technology, 121205 Skolkovo, Russia
3
Faculty of Chemistry, MV Lomonosov Moscow State University, 119991 Moscow, Russia
4
NN Blokhin Russian Cancer Research Center, Department of Oncogenes Regulation, 115478 Moscow, Russia
5
Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Neha Kaushik and Anthony C. Faber
Cancers 2022, 14(1), 181; https://doi.org/10.3390/cancers14010181
Received: 28 September 2021 / Revised: 15 December 2021 / Accepted: 20 December 2021 / Published: 30 December 2021
(This article belongs to the Special Issue Mechanism Underlying Tumor Relapse and Targeted Treatment Strategies)
Apoptosis is one of the best-known types of programmed cell death. This process is regulated by a number of genes and proteins, among which the Bcl-2 protein family plays a key role. This family includes anti- and proapoptotic proteins. Cancer cell resistance to apoptosis is commonly associated with overexpression of the antiapoptotic members of Bcl-2 family proteins, in particular, Bcl-2, Bcl-xL, and Mcl-1. Subsequently, these proteins represent perspective targets for anticancer therapy. Here, using an inhibitory approach, we found that Bak and Bcl-xL regulate sensitivity of cancer cells to Mcl-1 inhibition.
BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-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 cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition. View Full-Text
Keywords: Bcl-2 family proteins; BH3-mimetics; Mcl-1; cancer therapy; sensitivity Bcl-2 family proteins; BH3-mimetics; Mcl-1; cancer therapy; sensitivity
Show Figures

Figure 1

MDPI and ACS Style

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. Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors. Cancers 2022, 14, 181. https://doi.org/10.3390/cancers14010181

AMA Style

Senichkin VV, Pervushin NV, Zamaraev AV, Sazonova EV, Zuev AP, Streletskaia AY, Prikazchikova TA, Zatsepin TS, Kovaleva OV, Tchevkina EM, Zhivotovsky B, Kopeina GS. Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors. Cancers. 2022; 14(1):181. https://doi.org/10.3390/cancers14010181

Chicago/Turabian Style

Senichkin, Viacheslav V., Nikolay V. Pervushin, Alexey V. Zamaraev, Elena V. Sazonova, Anton P. Zuev, Alena Y. Streletskaia, Tatiana A. Prikazchikova, Timofei S. Zatsepin, Olga V. Kovaleva, Elena M. Tchevkina, Boris Zhivotovsky, and Gelina S. Kopeina. 2022. "Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors" Cancers 14, no. 1: 181. https://doi.org/10.3390/cancers14010181

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop