Abstract
Simple SummaryApoptosis 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.
Highlights
In multicellular organisms, apoptosis, an evolutionary conserved mechanism of programmed cell death (PCD), tightly controls cell number and tissue homeostasis
We have shown the potential markers for sensitivity of cancer cells to myeloid cell leukemia 1 (Mcl-1) inhibition and effective combinations of agents to overcome a resistance to BH3 mimetics to Mcl-1
We evaluated the activity of two BH3 mimetics to Mcl-1, A1210477 and S63845, which have been previously shown to effectively induce apoptosis in various cell lines [25,26]
Summary
Apoptosis, an evolutionary conserved mechanism of programmed cell death (PCD), tightly controls cell number and tissue homeostasis. Members of the B-cell lymphoma 2 (Bcl-2) family are key players in the regulation of the mitochondrial (intrinsic) pathway of apoptosis. This family includes both anti- and pro-apoptotic proteins [3]. The effectors of the Bcl-2 family, Bak and Bax, form pores in the outer mitochondrial membrane (OMM) [5], leading to the release of various pro-apoptotic factors into the cytosol, which is considered a point of no return in the mitochondrial-mediated apoptotic pathway [6]. BH3only pro-apoptotic proteins do not cause mitochondrial outer membrane permeabilization (MOMP) directly Instead, these proteins neutralize anti-apoptotic members of the Bcl-2 family and indirectly derepress Bak and Bax. some BH3-only proteins (Bim, truncated Bid) can directly activate pore-forming proteins; they are called “BH3only activators”. Proteins of another BH3-only subgroup (Puma, Noxa, Bad) do not directly activate Bak and Bax and are called “BH3-only sensitizers” [3,7]
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