Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level

Abstract

Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B-cell lymphoma-2 (Bcl-2) family regulate programmed cell death by the mitochondrial apoptosis pathway. In response to intracellular stress, the apoptotic balance is governed by interactions of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology 3)-only proteins, the pro-survival, and the pro-apoptotic executioner proteins. Changes in expression levels, stability, and functional impairment of pro-survival proteins can lead to an imbalance in tissue homeostasis. Their overexpression or hyperactivation can result in oncogenic effects. Pro-survival Bcl-2 family members carry out their function by binding the BH3 short linear motif of pro-apoptotic proteins in a modular way, creating a complex network of protein-protein interactions. Their dysfunction enables cancer cells to evade cell death. The critical role of Bcl-2 proteins in homeostasis and tumorigenesis, coupled with mounting insight in their structural properties, make them therapeutic targets of interest. A better understanding of gene expression, mutational profile, and molecular mechanisms of pro-survival Bcl-2 proteins in different cancer types, could help to clarify their role in cancer development and may guide advancement in drug discovery. Here, we shed light on the pro-survival Bcl-2 proteins in breast cancer using different bioinformatic approaches, linking -omics with structural data. We analyzed the changes in the expression of the Bcl-2 proteins and their BH3-containing interactors in breast cancer samples. We then studied, at the structural level, a selection of interactions, accounting for effects induced by mutations found in the breast cancer samples. We find two complexes between the up-regulated Bcl2A1 and two down-regulated BH3-only candidates (i.e., Hrk and Nr4a1) as targets associated with reduced apoptosis in breast cancer samples for future experimental validation. Furthermore, we predict L99R, M75R as damaging mutations altering protein stability, and Y120C as a possible allosteric mutation from an exposed surface to the BH3-binding site.

Hydroxy-α-sanshool Possesses Protective Potentials on H2O2-Stimulated PC12 Cells by Suppression of Oxidative Stress-Induced Apoptosis through Regulation of PI3K/Akt Signal Pathway

“…As is shown in Figure 8, the direct results of PI3K phosphorylation is the phosphorylation of AKT, which further affects the expression of Bcl-2 and Bax proteins. Bcl-2 and Bax are a group of proteins closely related to mitochondrial mediated apoptosis, among which the antiapoptotic protein Bcl-2 is a channel protein located on the mitochondrial membrane, which can inhibit the proapoptotic effect of Bax [44]. Activated p-AKT increased the expression of Bcl-2 and decreased the expression of Bax.…”

Breast Cancer Chemotherapeutic Options: A General Overview on the Preclinical Validation of a Multi-Target Ruthenium(III) Complex Lodged in Nucleolipid Nanosystems

“…Indeed, cell death evasion is currently recognized as a hallmark of cancer. Several findings demonstrate pro-proliferative and anti-apoptotic signals cooperating in initial mammary epithelial cells transformation, where the anti-apoptotic Bcl-2 proteins are considered to play an important role [47]. Consistently, BC spread is faster when correlated to Bcl-2 overexpression, as well as genetic Bax ablation promotes mammary tumor development [48].…”

“…In the context of cancer, genetic anomalies and unconventional microenvironments profit by endogenous pro-survival signaling to re-program and rewire metabolism to sustain survival, growth, and proliferation. It is now largely established that tumor is not simply a consequence of deregulated proliferation, but also of evasion from apoptosis, so the regulation of programmed cell death in cancer cells can be of critical importance in defining the overall growth or regression in response to treatments [45,47,152]. Besides being a major occurrence in the onset and progression of BC, malignant cells survival represents a crucial contributing factor also in clinical failure and chemoresistance development [153].…”

“…This suggests for AziRu the possible occurrence of mitochondrial molecular targets capable of restoring the switch of cancer cell death. In accordance, many tumors are responsive to Bcl-2 regulation as key inducer of proliferation, as well as increased Bax levels have been coupled to an enhanced response to chemotherapy [40,47,50]. At the mitochondrial level, Venetoclax is the first FDA-approved drug in cancer directly targeting the anti-apoptotic Bcl-2 protein to reactivate apoptosis.…”

<p>LncRNA DANCR-miR-758-3p-PAX6 Molecular Network Regulates Apoptosis and Autophagy of Breast Cancer Cells</p>

“…The inactivated caspase-9 is related to the tumor survival of triple-negative BC, and Bcl-2 is a vital factor in the antiapoptosis defense mechanism of BC. [27][28][29] Similarly, LC3B and Atg5 are positive regulators of autophagy, while Beclin-1 is negative regulator of autophagy. Among them, LC3B is tied to BC immune infiltration, Atg5 is tied to BC tumor occurrence and metastasis, and Beclin-1 is tied to BC patient survival and chemotherapy sensitivity.…”