bcl-2 interacting killer

Drug resistance always reduces the efficacy of chemotherapy, and the classical mechanisms of drug resistance include drug pump efflux and anti-apoptosis mediators-mediated non-pump resistance. In addition, the amphiphilic polymeric micelles with good biocompatibility and high stability have been proven to deliver the drug molecules inside the cavity into the cell membrane regardless of the efflux of the cell membrane pump. We designed a cyclodextrin (CD)-based polymeric complex to deliver chemotherapeutic doxorubicin (DOX) and Nur77ΔDBD gene for combating pumps and non-pump resistance simultaneously...

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon- γ (IFN- γ ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway...

Bcl-2-related ovarian killer (Bok) binds tightly to inositol 1,4,5-trisphosphate receptors (IP3 Rs). To better understand this interaction, we sought to elucidate the Bok binding determinants in IP3 R1, focusing on the ∼75 amino acid loop (residues 1882-1957) between α helices 72 and 73. Bioinformatic analysis revealed that the majority of this loop is intrinsically disordered, with two flanking regions of high disorder next to a low disorder central region (∼residues 1914-1926) that is predicted to contain two fused, disjointed transient helical elements...

Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains...

Decreased expression of proapoptotic genes can lead to the chemoresistenance in cancer therapy. Carboxyl-terminal binding protein 1 (CtBP1), a transcriptional corepressor with multiple oncogenic effects, has been previously identified to suppress the expression of two proapoptotic genes [ BAX (BCL2 associated X) and BIM (Bcl-2 interacting mediator of cell death)] by assembling a complex with the Forkhead box O3 (FOXO3a) transcription factor and the p300 histone acetyltransferase. However, the upstream regulatory signaling of the CtBP1-p300-FOXO3a complex is obscure, and the effects of changing this signaling on chemosensitivity in osteosarcoma are unknown...

Myeloid cell leukemia 1 ( MCL1 ) gene amplification occurs in a wide range of human cancers and protein overexpression associates with malignant cell growth and evasion of apoptosis. We recently reported that disrupting the interaction between the transmembrane domains of MCL1 and BCL-2 related ovarian killer (BOK) induces cell death, thereby suggesting a new target site for anti-tumorigenic strategies.

H1.2 is a key mediator of apoptosis following DNA double-strand breaks (DDSB). The link between H1.2 and canonical apoptotic pathways is unclear. One study found that H1.2 stimulates cytochrome c (Cyt c) release; in contrast, Apoptosis Inducing Factor (AIF) was found to be released in another study. The C-terminal domain (CTD) of H1.2 has been implicated in the latter pathway, but activation of the proapoptotic protein BCL-2 homologous antagonist/killer (BAK) is a common denominator in both pathways. This study aimed to determine whether the CTD of H1...

Naringenin (NG) is a natural antioxidant flavonoid which is isolated from citrus fruits, and has been reported to inhibit colon cancer proliferation. However, the effects of NG treatment on glioma remain to be elucidated. The present study aimed to explore the effects of NG on glioma in vitro and in vivo. Also, the interactions between NG and APO2 ligand (APO2L; also known as tumor necrosis factor-related apoptosis-inducing ligand) were investigated in glioma. A synergistic effect of NG and APO2L combination on apoptotic induction was observed, though glioma cells were insensitive to APO2L alone...

Apoptosis is fundamental to normal animal development and is the target for many anticancer therapies. Recent studies have explored the consequences of "failed apoptosis" where the apoptotic program is initiated but does not go to completion and does not cause cell death. Nevertheless, this failed apoptosis induces DNA double-strand breaks generating mutations that facilitate tumorigenesis. Whether failed apoptosis is relevant to clinical disease is unknown. BCL-2 interacting killer (BIK) is a stress-induced BH3-only protein that stimulates apoptosis in response to hormone and growth factor deprivation, hypoxia, and genomic stress...

The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality...

Copper (Cu) is an essential trace element involved in the normal physiological processes of animals. However, excessive exposure to Cu can produce numerous detrimental impacts. The aim of this study was to investigate the effects of Cu on oxidative stress and apoptosis as well as their relationship in the mouse liver. Four-week-old ICR mice ( n = 240) were randomly assigned to different Cu (Cu2+-CuSO4) treatment groups (0, 4, 8, and 16 mg/kg) for periods of 21 and 42 days. The high doses of Cu exposure could induce oxidative stress, by increasing the levels of reactive oxygen species (ROS) and protein carbonyls (PC) and decreasing the activities of antisuperoxide anion (ASA) and antihydroxyl radical (AHR) and content of glutathione (GSH), as well as activities and mRNA expression levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)...

Necroptosis is regarded as a new paradigm of cell death that plays a key role in the liver damage observed with selenium (Se) deficiency. Se deficiency has a significant impact on the livestock and poultry industries. Previous studies have confirmed that Se deficiency causes serious injury to the swine liver; however, it is unclear whether this liver damage is the result of necroptosis and apoptosis. To understand the damage induced by Se deficiency, swine were divided into a control group and Se-deficient group...

Auranofin is a gold complex categorized as an anti-rheumatic agent. Recently, several investigators suggested that auranofin may act as a potent anti-cancer drug for breast tumors. Nutlin-3a is a cis-imidazoline analog which prevents interaction between mouse double minute 2 homolog (MDM2) and the tumor suppressor p53. The aim of this study was to examine cell growth inhibition mediated by auranofin or nutlin-3a individually as well as in combination with MCF-7 and MDA-MB-231 cells. To assess any potential synergistic effects between auranofin and nutlin-3a, low concentrations of auranofin and nutlin-3a were simultaneously incubated with MCF-7 and MDA-MB-231 cells...

The mitochondria represent an integration and amplification hub for various death pathways including that mediated by granzyme B (GB), a granule enzyme expressed by cytotoxic lymphocytes. GB activates the proapoptotic B cell CLL/lymphoma 2 (Bcl-2) family member BH3-interacting domain death agonist (BID) to switch on the intrinsic mitochondrial death pathway, leading to Bcl-2-associated X protein (Bax)/Bcl-2 homologous antagonist/killer- (Bak-) dependent mitochondrial outer membrane permeabilization (MOMP), the dissipation of mitochondrial transmembrane potential (ΔΨm), and the production of reactive oxygen species (ROS)...

Bok (Bcl-2-related ovarian killer) is a member of the Bcl-2 protein family that governs the intrinsic apoptosis pathway, but the cellular role that Bok plays is controversial. Remarkably, endogenous Bok is constitutively bound to inositol 1,4,5-trisphosphate receptors (IP3 Rs) and is stabilized by this interaction. Here we report that despite the strong association with IP3 Rs, deletion of Bok expression by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease)-mediated gene editing does not alter calcium mobilization via IP3 Rs or calcium influx into the mitochondria...

Mitochondrial outer membrane permeabilization (MOMP) is a crucial initiating event in apoptosis that activates the caspase cascade to execute cell demise. The effector B-cell lymphoma 2 (BCL-2) antagonist killer (BAK) forms mitochondrial apoptotic pores to mediate MOMP. In healthy cells, BAK resides at the outer mitochondrial membrane as a dormant monomer. Upon direct interactions with the BCL-2 homology 3 (BH3)-only proapoptotic proteins during apoptosis, BAK undergoes conformational changes to form the active species associated with apoptotic pores...

The objective of the present study was to explore the molecular mechanism of apoptosis induced by sodium fluoride (NaF) in the mouse kidney by using the methods of flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and experimental pathology. 240 four-week-old ICR mice were randomly divided into 4 groups and exposed to different concentrations of NaF (0 mg kg-1 , 12 mg kg-1 , 24 mg kg-1 and 48 mg kg-1 ) for a period of 42 days. The results demonstrated that NaF increased cell apoptosis and the depolarization of the mitochondrial membrane potential (MMP), and that the mitochondrial pathway was involved in NaF-induced apoptosis...

Hyperplastic airway epithelial cells may be the cause for increased risk for lung cancer in patients with chronic lung diseases. The B-cell lymphoma 2 (Bcl-2) family member, Bcl-2-interacting killer (BIK), triggers cell death specifically in these hyperplastic cells because of adequate presence of Death-associated Protein Kinase 1 (DAPk1), BCL-2 Antagonist Killer (BAK), and Extracellular Signal-regulated Kinase 1/ 2 (ERK1/2). Therefore, BIK may be a useful tool to control the development of lung cancer in patients with chronic diseases...

AIMS: This study aimed to identify the mechanism of how MG-132 stimulates cell death in SEB-1 sebocytes. MATERIALS AND METHODS: TUNEL staining and annexin-FITC/PI flow cytometry were utilized to examine the apoptotic cell number of SEB-1 sebocytes and HaCaT keratinocytes upon MG-132 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment. MTT assay and CCK-8 assay monitored the proliferative rate and viability of both cell lines with different treatment...

BACKGROUND: Ischemia reperfusion injury (IRI) is associated with programmed cell death that promotes inflammation and organ dysfunction. Necroptosis is mediated by members of receptor interacting protein kinases (RIPK1/3). Inhibition of RIPK1/3 provides a pro-survival benefit in kidney IRI. Caspase-8 initiate apoptosis and contributes to IRI. We studied whether inhibiting both RIPK3 and caspase-8 would provide an additional benefit in kidney IRI. METHODS: A clamp was applied to the left kidney pedicle for 45 minutes followed by right kidney nephrectomy...