Inhibitor Of Apoptosis Protein Research Articles

Mechanistic and metabolic exploration of neohesperidin against lung cancer cell lines through ROS-mediated mitochondrial apoptosis: An in-silico and in-vitro approach.

Mechanistic and metabolic exploration of neohesperidin against lung cancer cell lines through ROS-mediated mitochondrial apoptosis: An in-silico and in-vitro approach.

Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve Is a Therapeutic Strategy for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth. However, CQ is limited in terms of specificity and potency. To find alternative anti-autophagy strategies, in this study, we performed a CRISPR-Cas9 loss-of-function screen in PDAC cell lines that identified the lipid kinase phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as a growth-promoting gene. PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment. PIKfyve inhibition caused lysosomal dysfunction, reduced autophagic flux, and led to the accumulation of autophagy-related proteins. Furthermore, PIKfyve inhibition blocked the compensatory increases in autophagic flux associated both with MEK inhibition and with direct RAS inhibition. Accordingly, combined inhibition of PIKfyve and the RAS-MAPK pathway showed robust growth suppression across a panel of KRAS-mutant PDAC models. Growth suppression was due, in part, to potentiated cell-cycle arrest and induction of apoptosis following loss of inhibitor of apoptosis proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC. Significance: PIKfyve inhibition effectively blocks autophagy in multiple models of KRAS-mutant pancreatic cancer and can synergize with inhibitors of members of the RAS-MAPK pathway, providing an effective combination strategy for pancreatic cancer.

Insights into biochemical, genotoxic, and molecular impacts, and molecular docking analysis-based possible mechanism of action of some essential oils against Culex pipiens larvae.

Insights into biochemical, genotoxic, and molecular impacts, and molecular docking analysis-based possible mechanism of action of some essential oils against Culex pipiens larvae.

The class A scavenger receptor member 3 (SCARA3) regulates cell apoptosis through X-linked apoptosis inhibitory protein (XIAP) in turbot (Scophthalmus maximus L.).

The class A scavenger receptor member 3 (SCARA3) regulates cell apoptosis through X-linked apoptosis inhibitory protein (XIAP) in turbot (Scophthalmus maximus L.).

Targeting the inhibitors of apoptosis proteins (IAPs) to combat drug resistance in cancers.

Inhibitors of Apoptosis Proteins (IAPs) are a family of anti-apoptotic proteins that play a pivotal role in apoptosis in general but also as oncoproteins in cancer progression and, more importantly, drug resistance. IAPs enable cancer cells to evade programmed cell death and adapt to therapeutic stress by inhibiting pro-apoptotic caspase activity as well as modulating pivotal survival pathways. Recent advancements in targeting IAPs, particularly through the use of SMAC (second mitochondria-derived activator of caspase) mimetics and other small-molecule antagonists or inhibitors, have opened new avenues for overcoming drug resistance in cancers. The current review attempted to summarize the status quo of IAPs' role in promoting chemotherapeutic drug resistance in various cancer treatments and discuss the most recent development of IAP-targeting therapies, particularly small-molecule inhibitors including their combinational strategies to enhance the sensitivity or achieve synergism to existing therapeutics. Additionally, we also outline the challenges and offer future perspectives for optimizing IAP-targeted approaches to improve clinical outcomes.

The critical role of X-linked inhibitor of apoptosis protein (XIAP) in tumor development.

X-linked inhibitor of apoptosis protein (XIAP) is the most potent endogenous member of the inhibitor of apoptosis protein family. XIAP exerts its anti-apoptotic effects by inhibiting both the death receptor pathway and mitochondrial pathway of apoptosis through various mechanisms such as directly binding to caspases, activating the nuclear factor kappa B (NF-κB) pathway, and other signaling pathways. These processes are closely related to tumor development and progression, making XIAP a therapeutic target for various types of cancer. This article will first review the structural characteristics and biological functions of XIAP, followed by its effects on tumors and an overview of XIAP-targeted inhibitors.

Dietary phytic acid damages the intestinal mucus barrier and structural integrity in the grass carp (Ctenopharyngodon idella).

Dietary phytic acid damages the intestinal mucus barrier and structural integrity in the grass carp (Ctenopharyngodon idella).

Comprehensive flow cytometry-based diagnosis of XIAP deficiency.

Deficiency of X-linked inhibitor of apoptosis protein (XIAP) is an X-linked recessive inborn error of immunity characterized by abnormal immune responses leading to inflammatory bowel disease and hemophagocytic lymphohistiocytosis. Although XIAP protein expression analysis by flow cytometry (XIAP flow) is commonly used to diagnose XIAP deficiency, certain variants may not affect the protein expression, thereby complicating the diagnostic process. XIAP is crucial for the nucleotide-binding and oligomerization domain 2 (NOD2) signaling pathway. In this study, we aimed to perform a comprehensive analysis of nine patients diagnosed with XIAP deficiency through genetic testing. In addition to XIAP flow, we employed a previously reported method utilizing muramyl dipeptide (MDP) stimulation, a specific agonist of NOD2, to quantitatively evaluate the downstream tumor necrosis factor-alpha (TNFα) production by flow cytometry in patient monocytes (MDP flow). The median mean fluorescence intensity in healthy controls with XIAP flow was 711 (95% confidence interval (CI), 653 to 815) compared to 195 (95% CI, 161-386) in patients with XIAP deficiency (p < 0.0001). The median percentage of TNFα-producing monocytes in controls with MDP flow was 29.1% (95% CI, 19.6 to 53.7), while in patients it was 0.34% (95% CI, 0.18 to 0.82) (p = 0.0008). The receiver operating characteristic curves demonstrated that both XIAP flow and MDP flow exhibited 100% sensitivity and specificity. Taken together, combining XIAP flow and MDP flow analyses allows for a highly accurate diagnosis. (230/250).

XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1

X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.

Design, synthesis, and biological evaluation of RIPK1-targeting PROTACs.

Cancer cells can hijack receptor-interacting protein kinase 1 (RIPK1) and exploit its scaffolding function to orchestrate pro-survival signaling and fuel immunosuppressive program. Accordingly, targeting RIPK1 for elimination has emerged as a promising anti-cancer strategy. Based on the RIPK1 inhibitor 4 previously reported by our group, we employed proteolysis targeting chimera (PROTAC) technology and designed a series of RIPK1 degraders. Structure-activity relationship (SAR) study revealed three types of ligands for E3 ligase - cereblon (CRBN), von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) - demonstrated varied efficacy in RIPK1 degradation of human and mouse cells. The VHL-based compound 18 exhibited potent RIPK1 degradation activity in both human and mouse cellular scenarios. Further biological evaluation confirmed that compound 18 potently induced RIPK1 degradation of I2.1 cells with a DC50 value of 274.4nM and maintained long-term and dramatic RIPK1 degradation within 72h. This study provided important insights into future development of RIPK1-PORTACs, and compound 18 was a promising RIPK1 degrader candidate.

Dietary AiiO-AIO6 mitigated Aeromonas hydrophila-induced intestinal inflammation in juvenile grass carp (Ctenopharyngodon idella) involving in NF-κB signaling and pyroptosis.

Dietary AiiO-AIO6 mitigated Aeromonas hydrophila-induced intestinal inflammation in juvenile grass carp (Ctenopharyngodon idella) involving in NF-κB signaling and pyroptosis.

Correlation Between Neuronal Apoptosis Inhibitory Protein (NAIP), SMN2, and SMA Phenotypes: A Tertiary Care Centre Experience From India.

SMN2 copy number fails to answer variability in the SMA phenotype completely. We aimed to evaluate the copy number variation in NAIP and SMN2: c.859G>C and A-44G variants as disease modifiers and their correlation with the SMA phenotype. Based on the motor milestones achieved, patients with homozygous deletion of SMN1 exon 7 were classified into SMA Types I-IV. The copy numbers of SMN1 exon 8, SMN2, and NAIP were determined using the MLPA assay. Sanger sequencing was performed for the SMN2 variants. The cohort of 142 patients included nearly equal numbers of patients of SMA Types I, II, and III. The disease severity correlated with the SMN2 and NAIP copy number, with a lower copy number predicting a worse outcome. In addition, we evaluated the SMA genotype (SMN1 exon 8, SMN2 copy number, and NAIP copy number) as a predictor of SMA severity and found that most of the SMA Type I patients had a genotype of 0-2-0, SMA Type II patients had a genotype of 0-3-1, Type III patients had a genotype of 0-3-2 and 0-3-1, and Type IV patients had a genotype of 0-4-2. None of the patients from the cohort had the two modifier variants. The combined genotype of SMN1 exon 8 copy number-SMN2 copy number-NAIP copy number could accurately predict the SMA phenotype. The absence of SMN2: c.859G>C and A-44G variants in any of our patients points to the rarity of these variants in the Indian population.

FlaA N/C attenuates radiation-induced lung injury by promoting NAIP/NLRC4/ASC inflammasome autophagy and inhibiting pyroptosis

BackgroundRadiation-induced lung injury (RILI) is the most common complication experienced by patients with thoracic tumors after radiotherapy. Among patients receiving thoracic tumor radiotherapy, 14.6–37.2% develop RILI. RILI is characterized by an acute inflammatory response; however, the exact mechanism remains unclear and an ideal drug is still lacking. In this study, we investigated the protective effects of flagellin A with linked C- and N-terminal ends (FlaA N/C) against the development of RILI.MethodsMice and bronchial epithelial cells were exposed to radiation (15 Gy) after FlaA N/C treatment. Lung injury, bronchial epithelial cell injury, and RILI were assessed by histological evaluation in vivo and cell viability and cell death detection in vitro. Pyroptosis was assessed by western blotting (WB), immunofluorescence (IF), and immunohistochemistry (IHC). To explore the molecular mechanisms by which FlaA N/C inhibits RILI, conditional Beclin 1 (Beclin1+/−) and NLR family CARD domain-containing protein 4 (Nlrc4)-knockout (Nlrc4−/−) mice were generated. An autophagy inhibitor was used for in vitro cell assays, and pyroptosis indicators were detected. Data were analyzed using one-way analysis of variance.ResultsFlaA N/C attenuated radiation-induced lung tissue damage, pro-inflammatory cytokine release, and pyroptosis in vivo and cell viability, cell death, and pyroptosis in vitro. Mechanistically, FlaA N/C activated the neuronal apoptosis inhibitory protein (NAIP)/NLRC4/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasome, which was then degraded during Beclin 1-mediated autophagy. Deletion of the FlaA N/C D0 domain reversed the inhibitory effect of FlaA N/C on radiation-induced pyroptosis in vivo and in vitro. Similarly, Nlrc4-knockout in vivo or inhibition of autophagy in vitro eliminated the protective effects of FlaA N/C against radiation-induced pyroptosis.ConclusionsThese results indicate that FlaA N/C attenuates RILI by promoting NAIP/NLRC4/ASC inflammasome autophagy and inhibiting pyroptosis. This study provides a potential approach for RILI intervention.

Molecular Docking of Lactoferrin with Apoptosis-Related Proteins Insights into Its Anticancer Mechanism.

Human Lactoferrin (hLf), a multifunctional glycoprotein, has been analyzed through molecular docking to evaluate its role in apoptosis regulation and its potential as an anticancer agent. The docking results highlight XIAP (X-linked Inhibitor of Apoptosis Protein) and Caspase-3 as the most reliable targets, where hLf disrupts XIAP's inhibition of Caspase-3 and Caspase-9, potentially restoring apoptotic signaling; hLf also stabilizes Caspase-3, enhancing its activation in intrinsic and extrinsic pathways. Weaker interactions were observed with Fas, Bcl-2, and Akt. hLf's role in Fas signaling is likely due to expression upregulation rather than direct binding. In contrast, its binding to Bcl-2 may disrupt anti-apoptotic function, and its interaction with Akt suggests interference with pro-survival signaling. These findings suggest that hLf may promote apoptosis by enhancing caspase activation and modulating key apoptotic regulators, supporting its potential use in cancer treatment. However, further experimental validation is needed to confirm these interactions and their therapeutic implications.

CDK4/6 inhibitors upregulate cIAP1/2, and Smac mimetic LCL161 enhances their antitumor effects in cholangiocarcinoma cells

Cholangiocarcinoma (CCA) is a highly aggressive bile duct cancer with a poor prognosis and high mortality rates, primarily due to the lack of early diagnosis and effective treatments. We have shown that cyclin D and CDK4/6, key regulators of cell cycle progression, are highly expressed in CCA patients. Moreover, high levels of cyclin D, CDK4, and CDK6 are associated with shorter survival in CCA patients, suggesting that cyclin D and CDK4/6 might be potential targets for CCA therapy. However, we have demonstrated that CDK4/6 inhibitor palbociclib monotherapy is less effective in CCA cells. We have identified Cellular Inhibitor of Apoptosis Proteins 1 and 2 (cIAP1/2), NF-κB target genes that their expression is associated with shorter survival in CCA patients, as potential key regulators of the CDK4/6 inhibitor response. We showed that palbociclib, a CDK4/6 inhibitor, increases phosphorylated p65 and its nuclear translocation, resulting in cIAP1/2 upregulation in CCA cells. Therefore, we hypothesized that the combination of a cIAP1/2 antagonist and a CDK4/6 inhibitor might enhance the CDK4/6 inhibitor response. Interestingly, combined treatment with the Smac mimetic LCL161, a cIAP1/2 antagonist, and palbociclib synergistically inhibits cell proliferation and induces cell death in both 2D monolayer and 3D spheroid CCA cultures. We further showed that this combination treatment has less effect on non-tumor cholangiocytes and human peripheral blood mononuclear cells (PBMCs). Our findings demonstrate for the first time that the combined treatment of Smac mimetics and CDK4/6 inhibitors is a promising novel targeted therapy for CCA patients.

Synthetic Lethality of SHP2 and XIAP Suppresses Proliferation and Metastasis in KRAS-mutant Nonsmall Cell Lung Cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are associated with poor prognosis and poor response to standard therapeutic regimens in patients with nonsmall cell lung cancer (NSCLC). Identification of novel synthetic lethal partners in oncogenic KRAS is an alternative therapeutic strategy for KRAS-mutant malignancies. After high-throughput screening against a preclinical/clinical compound library, embelin, a known X-linked inhibitor of apoptosis protein (XIAP) inhibitor, specifically inhibits the catalytic activity and phosphorylation of Src homology domain 2 containing tyrosine phosphatase 2 (SHP2) in KRAS-mutant NSCLC cells. Pharmacological inhibition and genetic knockdown of XIAP and SHP2 induce synthetic lethality in KRAS-mutated NSCLC cells and xenograft animal models. Mechanistically, dual inhibition of XIAP and SHP2 by embelin lessens the proliferation and metastasis, activates senescence and endogenous apoptosis, inhibits cancer-related RAS/mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K)/AKT, Janus kinase/signal transducers and activators of transcription (JAK/STAT), wingless-related integration site (Wnt), and nuclear factor kappa B (NF-κB) signaling pathways, and overcomes compensatory feedback in the MAPK signals through the modulation of mitogen-inducible gene-6 (MIG-6) and SPROUTY2 (SPRY2). Collectively, SHP2 and XIAP are potential synthetic lethal partners, and embelin warrants further development as a novel therapeutic option for alleviating KRAS-mutant NSCLC by cotargeting SHP2 and XIAP.

Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy

Glioblastomas (GBM) are routinely treated with high doses of ionizing radiation (IR), yet these tumors recur quickly, and the recurrent tumors are highly therapy resistant. Here, we report that IR-induced senescence of tumor cells counterintuitively spurs GBM recurrence, driven by the senescence-associated secretory phenotype (SASP). We find that irradiated GBM cell lines and patient derived xenograft (PDX) cultures senesce rapidly in a p21-dependent manner. Senescent glioma cells upregulate SASP genes and secrete a panoply of SASP factors, prominently interleukin IL-6, an activator of the JAK-STAT3 pathway. These SASP factors collectively activate the JAK-STAT3 and NF-κB pathways in non-senescent GBM cells, thereby promoting tumor cell proliferation and SASP spreading. Transcriptomic analyses of irradiated GBM cells and the TCGA database reveal that the cellular inhibitor of apoptosis protein 2 (cIAP2), encoded by the BIRC3 gene, is a potential survival factor for senescent glioma cells. Senescent GBM cells not only upregulate BIRC3 but also induce BIRC3 expression and promote radioresistance in non-senescent tumor cells. We find that second mitochondria-derived activator of caspases (SMAC) mimetics targeting cIAP2 act as novel senolytics that trigger apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells. Finally, using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. Taken together, our results clearly indicate that significant improvement in GBM patient survival may become possible in the clinic by eliminating senescent cells arising after radiotherapy.

The miR-6779/XIAP axis alleviates IL-1β-induced chondrocyte senescence and extracellular matrix loss in osteoarthritis.

Osteoarthritis (OA) is a long-term degenerative joint disease worsening over time. Aging and chondrocyte senescence contribute to OA progression. MicroRNAs have been confirmed to regulate different cellular processes. They contribute to OA pathology and may help to identify novel biomarkers and therapies for OA. This study used bioinformatics and experimental investigations to analyze and validate differentially expressed miRNAs in OA that might affect chondrocyte apoptosis and senescence. miR-6779 was found to be significantly down-regulated in OA. Seventy-six of the predicted and miR-6779 targeted genes and the OA-associated disease genes overlapped, and these were enriched in cell proliferation, cell apoptosis, and cell cycle. miR-6779 overexpression remarkably attenuated IL-1β effects on chondrocytes by reducing MMP3 and MMP13 levels, promoting cell apoptosis, suppressing cell senescence, and increasing caspase-3, caspase-9 and reducing P16 and P21 levels. miR-6779 targeted inhibition of X-linked inhibitor of apoptosis protein (XIAP) expression. XIAP knockdown partially improved IL-1β-induced chondrocyte senescence and dysfunction. Lastly, when co-transfected with a miR-6779 agomir, the XIAP overexpression vector partially attenuated the effects of miR-6779 overexpression on chondrocytes; miR-6779 improved IL-1β-induced senescence and dysfunction in chondrocytes through targeting XIAP. miR-6779 is down-regulated, and XIAP is up-regulated in OA cartilage and IL-1β-treated chondrocytes. miR-6779 inhibits XIAP expression, thereby promoting senescent chondrocyte cell apoptosis and reducing chondrocyte senescence and ECM loss through XIAP.

The IAP antagonist tolinapant enhances the anti-tumor activity of cell therapies.

The IAP antagonist tolinapant enhances the anti-tumor activity of cell therapies.

Curcumin Analog GO-Y030 Triggers JNK and p38 Signalling to Activate Apoptotic Cascades in Human Osteosarcoma Cells.

Osteosarcoma, the most common primary bone cancer in adolescents, often carries a grim prognosis due to its high metastatic potential. Due to its low bioavailability, curcumin limits its adjuvant efficacy in improving prognosis and long-term survival in osteosarcoma patients. To investigate apoptosis induced by the synthesised curcumin analog GO-Y030 in human osteosarcoma cells, flow cytometry, annexin V-fluorescein isothiocyanate-labelled/propidium iodide staining, human apoptosis array, and Western blotting were used. GO-Y030 dose-dependently reduced viability and induced sub-G1 arrest and apoptosis in human osteosarcoma U2OS and 143B cells. GO-Y030 significantly activated caspases 8, 9, and 3, while suppressing cellular inhibitors of apoptosis protein 1 (cIAP-1) and X-chromosome-linked IAP. GO-Y030 increased the phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38. Inhibitors of JNK (JNK-IN-8) and p38 (SB203580) suppressed GO-Y030-induced cleavage of caspases 8, 9, and 3, whereas co-treatment with the ERK inhibitor (U0126) did not lessen their activation. Overall, GO-Y030 triggers both extrinsic and intrinsic apoptotic cascades in U2OS and 143B cells by activating the JNK1/2 and p38 pathways, shedding light on its mechanism of action against human osteosarcoma cells.