Dataset Information

Docking-based approach for identification of mutations that disrupt binding between Bcl-2 and Bax proteins: Inducing apoptosis in cancer cells.

ABSTRACT: BACKGROUND:Inducing apoptosis in cancer cells is an important step for the successful treatment of cancer patients. Bcl-2 is an antiapoptotic protein which determines apoptosis by interacting with proapoptotic members of the Bcl-2 family. Exome sequencing has identified Bcl-2 and Bax missense mutations in more than 40 cancer types. However, a little information is available about the functional impact of each Bcl-2 and Bax mutation on the pathogenesis of cancer. METHODS:The mutational data from cancer tissues and cell lines were retrieved from the cBioPortal web resource. The 13 mutated Bcl-2 and wild-type Bax complexes with experimentally verified binding were identified from previous studies wherein, binding for all complexes was reportedly disrupted except one. Several protein-protein docking methods such as ClusPro, HDOCK, PatchDock, FireDock, InterEVDock2 and several mutation prediction methods such as PolyPhen-2, SIFT, and OncoKB have been used to predict the effect of mutation to disrupt the binding between Bcl-2 and Bax. The result obtained was compared with the known experimental data. RESULTS:The protein-protein docking method, ClusPro, employed in the present study confirmed that the binding affinity of 11 out of 13 complexes decreases. Similarly, binding affinity computed for all the 10 wild-type Bcl-2 and mutated Bax complexes agreed with experimentally verified results. CONCLUSION:Several methods like PolyPhen-2, SIFT, and OncoKB have been developed to predict cancer-associated or deleterious mutations, but no method is available to predict apoptosis-inducing mutations. Thus, in this study, we have examined the mutations in Bcl-2 and Bax proteins that disrupt their binding, which is crucial for inducing apoptosis to eradicate cancer. This study suggests that protein-protein docking methods can play a significant role in the identification of hotspot mutations in Bcl-2 or Bax that can disrupt their binding with wild-type partner to induce apoptosis in cancer cells.

SUBMITTER: Raghav PK

PROVIDER: S-EPMC6825947 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Docking-based approach for identification of mutations that disrupt binding between Bcl-2 and Bax proteins: Inducing apoptosis in cancer cells.

Raghav Pawan Kumar PK Kumar Rajesh R Kumar Vinod V Raghava Gajendra P S GPS

Molecular genetics & genomic medicine 20190906 11

<h4>Background</h4>Inducing apoptosis in cancer cells is an important step for the successful treatment of cancer patients. Bcl-2 is an antiapoptotic protein which determines apoptosis by interacting with proapoptotic members of the Bcl-2 family. Exome sequencing has identified Bcl-2 and Bax missense mutations in more than 40 cancer types. However, a little information is available about the functional impact of each Bcl-2 and Bax mutation on the pathogenesis of cancer.<h4>Methods</h4>The mutati ...[more]

PMID: 31490001

Similar Datasets

Project description:Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110?-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.

Project description:BackgroundAcute kidney injury (AKI) caused by bee stings is common, with characteristics of acute onset, severe illness, and high mortality. Melittin, a major component of bee venom, has been considered to play a key role in bee sting related AKI. This study aims to illustrate whether melittin could lead to apoptosis of renal tubular epithelial cells (RTECs) and to investigate its mechanism.MethodsIn vivo, 45 mice were randomly divided into the melittin group (n=30, injected with melittin into the tail vein according to the total dose of 4.0 ug/g weight) and the control group (n=15, injected with the same volume of saline into the tail vein). In vitro, human RTECs (HK-2) were cultured and treated with melittin (2ug/ml or 4ug/ml) and TNF-α (10ng/ml). Biochemical analysis, HE stains, and electron microscope were performed to evaluate renal function and pathological changes. TUNEL stains and flow cytometry were performed to detect apoptosis. Real-time PCR was performed to detect mRNA levels of Bax, Bcl-2, and TNF-α. Simple western assay and immunohistochemical (IH) and immunofluorescent (IF) stains were performed for protein detection.ResultsMelittin successfully induced AKI in mice. Compared with the control group, obvious injury and apoptosis of RTECs were observed in the melittin group; the mRNA and protein expressions of Bax were significantly increased, while the expression of Bcl-2 was significantly decreased. The serum TNF-αlevel in melittin group was significantly higher than that in control group. In vitro, the results confirmed that melittin can cause HK-2 cells apoptosis. The trends of expression of Bax and Bcl-2 were consistent with the results in vivo. The levels of TNF-α mRNA and protein by PCR and Western blot were significantly higher in melittin group than those in control group.ConclusionMelittin can lead to the apoptosis of RTECs, which may be mediated by upregulating the expression of Bax/Bcl-2 and activating the TNF-α signaling pathway.

Dataset Information

Docking-based approach for identification of mutations that disrupt binding between Bcl-2 and Bax proteins: Inducing apoptosis in cancer cells.

Publications

Docking-based approach for identification of mutations that disrupt binding between Bcl-2 and Bax proteins: Inducing apoptosis in cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets