Polyphyllin D punctures hypertrophic lysosomes to reverse drug resistance of hepatocellular carcinoma by targeting acid sphingomyelinase.

Hypertrophic lysosomes are critical for tumor progression and drug resistance; however, effective and specific lysosome-targeting compounds for cancer therapy are lacking. Here we conducted a lysosomotropic pharmacophore-based in silico screen in a natural product library (2,212 compounds), and identified polyphyllin D (PD) as a novel lysosome-targeted compound. PD treatment was found to cause lysosomal damage, as evidenced by the blockade of autophagic flux, loss of lysophagy, and the release of lysosomal contents, thus exhibiting anticancer effects on hepatocellular carcinoma (HCC) cell both in vitro and in vivo. Closer mechanistic examination revealed that PD suppressed the activity of acid sphingomyelinase (SMPD1), a lysosomal phosphodieserase that catalyzes the hydrolysis of sphingomyelin to produce ceramide and phosphocholine, by directly occupying its surface groove, with Trp148 in SMPD1 acting as a major binding residue; this suppression of SMPD1 activity irreversibly triggers lysosomal injury and initiates lysosome-dependent cell death. Furthermore, PD-enhanced lysosomal membrane permeabilization to release sorafenib, augmenting the anticancer effect of sorafenib both in vivo and in vitro. Overall, our study suggests that PD can potentially be further developed as a novel autophagy inhibitor, and a combination of PD with classical chemotherapeutic anticancer drugs could represent a novel therapeutic strategy for HCC intervention.

ZSWIM1 Promotes the Proliferation and Metastasis of Lung Adenocarcinoma Cells through the STK38/MEKK2/ERK1/2 Axis.

Investigating the functions of the proteins with no or less functional annotations is an important goal of the HPP (Human Proteome Project) Grand Project. In this study, we investigated the function of such a protein, ZSWIM1 (C20orf162), its gene located on chromosome 20. Its expression is upregulated in lung adenocarcinoma compared with the adjacent normal tissues and negatively correlated with the overall survival. Overexpressing ZSWIM1 markedly promotes the proliferation, migration, invasion as well as epithelial-to-mesenchymal transition in lung adenocarcinoma cells, while knocking down ZSWIM1 functions oppositely. The interactome of ZSWIM1 was identified by immunoprecipitation-mass spectrometry, and we verified the interaction of ZSWIM1 with the potential partner, STK38. ZSWIM1 antagonized the function of STK38. Mechanically, ZSWIM1 promoted the activation of MEKK2/ERK1/2 pathway through interacting with STK38, leading to the release of MEKK2. Taken together, ZSWIM1 can be annotated as an oncogene in lung adenocarcinoma, and the STK38/MEKK2/ERK1/2 axis mediates its promoting role in lung adenocarcinoma.

Exosomal PPARγ derived from macrophages suppresses LPS-induced peritonitis by negative regulation of CD14/TLR4 axis.

BACKGROUND: Intercellular communication between macrophages and peritoneal mesothelial cells (PMCs) has been suggested as a key factor regulating peritonitis development. Here, we explored whether PPARγ (peroxisome proliferator-activated receptor gamma) can be packaged into macrophage exosomes to mediate intercellular communication and regulate peritonitis. METHODS: Macrophage exosomes were isolated by ultracentrifugation and identified by nanoparticle tracking analysis and transmission electron microscopy. Proteomic analysis of macrophage-derived exosomes was performed using mass spectrometry. Co-culture models of supernatants or exosomes with PMCs, as well as a mouse peritonitis model induced by lipopolysaccharide (LPS), were employed. RESULTS:  In this study, using stable Raw264.7 cells overexpressing GFP-FLAG-PPARγ (OE-PPARγ), we found that PPARγ inhibited LPS-induced inflammatory responses in Raw264.7 cells and that PPARγ was incorporated into macrophage exosomes during this process. Overexpression of PPARγ mainly regulated the secretion of differentially expressed exosomal proteins involved in the biological processes of protein transport, lipid metabolic process, cell cycle, apoptotic process, DNA damage stimulus, as well as the KEGG pathway of salmonella infection. Using co-culture models and mouse peritonitis model, we showed that exosomes from Raw264.7 cells overexpressing PPARγ inhibited LPS-induced inflammation in co-cultured human PMCs and in mice through downregulating CD14 and TLR4, two key regulators of the salmonella infection pathway. Pretreatment of the PPARγ inhibitor GW9662 abolished the anti-inflammatory effect of exosomes from Raw264.7 OE-PPARγ cells on human PMCs. CONCLUSIONS: These results suggested that overexpression of PPARγ largely altered the proteomic profile of macrophage exosomes and that exosomal PPARγ from macrophages acted as a regulator of intercellular communication to suppress LPS-induced inflammatory responses in vitro and in vivo via negatively regulating the CD14/TLR4 axis.

Biphasic regulation of transcriptional surge generated by the gene feedback loop in a two-component system.

MOTIVATION: Transcriptional surges generated by two-component systems (TCSs) have been observed experimentally in various bacteria. Suppression of the transcriptional surge may reduce the activity, virulence and drug resistance of bacteria. In order to investigate the general mechanisms, we use a PhoP/PhoQ TCS as a model system to derive a comprehensive mathematical modeling that governs the surge. PhoP is a response regulator, which serves as a transcription factor under a phosphorylation-dependent modulation by PhoQ, a histidine kinase. RESULTS: Our model reveals two major signaling pathways to modulate the phosphorylated PhoP (P-PhoP) level, one of which promotes the generation of P-PhoP, while the other depresses the level of P-PhoP. The competition between the P-PhoP-promoting and the P-PhoP-depressing pathways determines the generation of the P-PhoP surge. Furthermore, besides PhoQ, PhoP is also a bifunctional modulator that contributes to the dynamic control of P-PhoP state, leading to a biphasic regulation of the surge by the gene feedback loop. In summary, the mechanisms derived from the PhoP/PhoQ system for the transcriptional surges provide a better understanding on such a sophisticated signal transduction system and aid to develop new antimicrobial strategies targeting TCSs. AVAILABILITY AND IMPLEMENTATION: https://github.com/jianweishuai/TCS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PPARγ alleviates peritoneal fibrosis progression along with promoting GLUT1 expression and suppressing peritoneal mesothelial cell proliferation.

OBJECTIVE: Peritoneal fibrosis (PF) is commonly induced by bioincompatible dialysate exposure during peritoneal dialysis, but the underlying mechanisms remain elusive. This study aimed to investigate the roles of peroxisome proliferator-activated receptor gamma (PPARγ) in PF pathogenesis. METHODS: Rat and cellular PF models were established by high glucose dialysate and lipopolysaccharide treatments. Serum creatinine, urea nitrogen, and glucose contents were detected by ELISA. Histological evaluation was done through H&E and Masson staining. GLUT1, PPARγ, and other protein expression were measured by qRT-PCR, western blotting, and IHC. PPARγ and GLUT1 subcellular distribution were detected using confocal microscopy. Cell proliferation was assessed by MTT and Edu staining. RESULTS: Serum creatinine, urea nitrogen and glucose, and PPARγ and GLUT1 expression in rat PF model were reduced by PPARγ agonists Rosiglitazone or 15d-PGJ2 and elevated by antagonist GW9662. Rosiglitazone or 15d-PGJ2 repressed and GW9662 aggravated peritoneal fibrosis in rat PF model. PPARγ and GLUT1 were mainly localized in nucleus and cytosols of peritoneal mesothelial cells, respectively, which were reduced in cellular PF model, enhanced by Rosiglitazone or 15d-PGJ2, and repressed by GW9662. TGF-ß and a-SMA expression was elevated in cellular PF model, which was inhibited by Rosiglitazone or 15d-PGJ2 and promoted by GW9662. PPARγ silencing reduced GLUT1, elevated a-SMA and TGF-b expression, and promoted peritoneal mesothelial cell proliferation, which were oppositely changed by PPARγ overexpression. CONCLUSION: PPARγ inhibited high glucose-induced peritoneal fibrosis progression through elevating GLUT1 expression and repressing peritoneal mesothelial cell proliferation.

Different response modes and cooperation modulations of blue-light receptors in photomorphogenesis.

Cryptochromes photoreceptors, CRY1 and CRY2 in Arabidopsis, mediate blue light responses in plants and metazoa. The signalling interactions underlying photomorphogenesis of cryptochromes action have been extensively studied in experiment, expecting a systematical analysis of the dynamic mechanisms of photosensory signalling network from a global view. In this study, we developed a signalling network model to quantitatively investigate the different response modes and cooperation modulations on photomorphogenesis for CRY1 and CRY2 under blue light. The model shows that the different modes of time-dependent and fluence-rate-dependent phosphorylations for CRY1 and CRY2 are originated from their different phosphorylation rates and degradation rates. Our study indicates that, due to the strong association between blue-light inhibitor of cryptochromes (BIC) and CRY2, BIC negatively modulates CRY2 phosphorylation, which was confirmed by our experiment. The experiment also validated the model prediction that the time-dependent BIC-CRY1 and the fluence-rate-dependent BIC-CRY2 are both bell-shaped under blue light. Importantly, the model proposes that the COP1-SPA abundance can strongly inhibit the phosphorylation response of CRY2, resulting in the positive regulation of CRY2 phosphorylation by CRY1 through COP1-SPA. The model also predicts that the CRY1-HY5 axis, rather than CRY2-HY5 pathway, plays a dominant role in blue-light-dependent photomorphogenesis.

ANXA1-GSK3ß interaction and its involvement in NSCLC metastasis.

Although initially discovered and extensively studied for its role in inflammation, Annexin A1 (ANXA1) has been reported to be closely related to cancer in recent years, and its role in cancer is specific to tumor types and tissues. In the present study, we identified ANXA1 as an interaction partner of glycogen synthase kinase 3 beta (GSK3ß), a multi-functional serine/threonine kinase tightly associated with cell fate determination and cancer, and assessed the functional significance of GSK3ß-ANXA1 interaction in the metastasis of non-small cell lung cancer (NSCLC). We confirmed the interaction between GSK3ß and ANXA1 in vitro and in H1299 and A549 cells by Glutathione-S-transferase (GST) pull-down assay and co-immunoprecipitation. We found that ANXA1 negatively regulated the phosphorylation of GSK3ß and inhibited the epithelial-mesenchymal transformation (EMT) process and migration and invasion of NSCLC cells. By functional rescue assay, we confirmed that ANXA1 inhibited EMT through the regulation of GSK3ß activity and thereby inhibited the migration and invasion of NSCLC cells. Our study sheds light on the function of ANXA1 and GSK3ß and provides new elements for the understanding of NSCLC pathogenesis.

Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2.

To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect need to be further assessed in a prospective clinical trial.

YAP mediates the positive regulation of hnRNPK on the lung adenocarcinoma H1299 cell growth.

Lung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) accounts for 80%-85% of diagnostic cases. The molecular mechanisms of NSCLC pathogenesis are not well understood. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a multifunctional protein that regulates gene expression and signal transduction and closely associated with tumorigenesis, but its mechanism of action in the pathogenesis of NSCLC is unclear. In this study, we observed that the expression pattern of hnRNPK in H1299 lung adenocarcinoma cells varied depending on the cell density in culture. Moreover, hnRNPK stimulated the ability of proliferation and colony formation of H1299 cells, which is important for the multilayered cell growth in culture. We further investigated whether there is an association between hnRNPK and the elements involved in the cell contact inhibition pathway. By using quantitative reverse transcriptase-polymerase chain reaction assay and a YAP activity reporter system, we found that hnRNPK upregulated the mRNA and protein levels and transcriptional activity of Yes-associated protein 1 (YAP), a master negative regulator of Hippo contact inhibition pathway. Furthermore, YAP knockdown with siRNA abolished the stimulatory effect of hnRNPK on H1299 cell proliferation. These results suggested that YAP could be one of the effectors of hnRNPK. Our data may provide new clues for further understanding the biological functions of hnRNPK, particularly in the context of lung adenocarcinoma oncogenesis.

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK-3ß/ß-catenin signaling.

Osteosarcoma (OS) is the most malignant primary bone tumor in children and adolescents with limited treatment options and poor prognosis. Recently, aberrant expression of Runx2 has been found in OS, thereby contributing to the development, and progression of OS. However, the upstream signaling molecules that regulate its expression in OS remain largely unknown. In the present study, we first confirmed that the inhibition of HSP90 with 17-AAG caused significant apoptosis of OS cells via a caspase-3-dependent mechanism, and that inhibition or knockdown of HSP90 by 17-AAG or siRNAs significantly suppressed mRNA and protein expression of Runx2. Furthermore, we provided evidence that Runx2 was transcriptionally regulated by HSP90 when using MG132 and CHX chase assay. We also demonstrated that ß-catenin was overexpressed in OS tissue, and that knockdown of ß-catenin induced pronounced apoptosis of OS cells in the presence or absence of 17-AAG. Interestingly, this phenomenon was accompanied with a significant reduction of Runx2 and Cyclin D1 expression, indicating an essential role of Runx2/Cyclin D1 in 17-AAG-induced cells apoptosis. Moreover, we demonstrated that the apoptosis of OS cells induced by 17-AAG did require the involvement of the AKT/GSK-3ß/ß-catenin signaling pathway by using pharmacological inhibitor GSK-3ß (LiCl) or siGSK-3ß. Our findings reveal a novel mechanism that Runx2 is transcriptionally regulated by HSP90 via the AKT/GSK-3ß/ß-catenin signaling pathway, and by which leads to apoptosis of OS cells.

Andrographolide Induces Cell Cycle Arrest and Apoptosis of Chondrosarcoma by Targeting TCF-1/SOX9 Axis.

Chondrosarcoma is the second most malignant bone tumor with poor prognosis and limited treatment options. Thus, development of more effective treatments has become urgent. Recently, natural compounds derived from medicinal plants have emerged as promising therapeutic options via targeting multiple key cellular molecules. Andrographolide (Andro) is such a compound, which has previously been shown to induce cell cycle arrest and apoptosis in several human cancers. However, the molecular mechanism through which Andro exerts its anti-cancer effect on chondrosarcoma remains to be elucidated. In the present study, we showed that Andro-induced G2/M cell cycle arrest of chondrosarcoma by fine-tuning the expressions of several cell cycle regulators such as p21, p27, and Cyclins, and that prolonged treatment of cells with Andro caused pronounced cell apoptosis. Remarkably, we found that SOX9 was highly expressed in poor-differentiated chondrosarcoma, and that knockdown of SOX9 suppressed chondrosarcoma cell growth. Further, our results showed that Andro dose-dependently down-regulated SOX9 expression in chondrosarcoma cells. Concomitantly, an inhibition of T cell factor 1 (TCF-1) mRNA expression and an enhancement of TCF-1 protein degradation by Andro were observed. In contrast, the expression and subcellular localization of ß-catenin were not altered upon the treatment of Andro, suggesting that ß-catenin might not function as the primary target of Andro. Additionally, we provided evidence that there was a mutual regulation between TCF-1 and SOX9 in chondrosarcoma cells. In conclusion, these results highlight the potential therapeutic effects of Andro in treatment of chondrosarcoma via targeting the TCF-1/SOX9 axis. J. Cell. Biochem. 118: 4575-4586, 2017. © 2017 Wiley Periodicals, Inc.

Differential protein analysis of serum exosomes post-intravenous immunoglobulin therapy in patients with Kawasaki disease.

BACKGROUND: Kawasaki disease, which is characterised by systemic vasculitides accompanied by acute fever, is regularly treated by intravenous immunoglobulin to avoid lesion formation in the coronary artery; however, the mechanism of intravenous immunoglobulin therapy is unclear. Hence, we aimed to analyse the global expression profile of serum exosomal proteins before and after administering intravenous immunoglobulin. METHODS: Two-dimensional electrophoresis coupled with mass spectrometry analysis was used to identify the differentially expressed proteome of serum exosomes in patients with Kawasaki disease before and after intravenous immunoglobulin therapy. RESULTS: Our analysis revealed 69 differential protein spots in the Kawasaki disease group with changes larger than 1.5-fold and 59 differential ones in patients after intravenous immunoglobulin therapy compared with the control group. Gene ontology analysis revealed that the acute-phase response disappeared, the functions of the complement system and innate immune response were enhanced, and the antibacterial humoral response pathway of corticosteroids and cardioprotection emerged after administration of intravenous immunoglobulin. Further, we showed that complement C3 and apolipoprotein A-IV levels increased before and decreased after intravenous immunoglobulin therapy and that the insulin-like growth factor-binding protein complex acid labile subunit displayed reverse alteration before and after intravenous immunoglobulin therapy. These observations might be potential indicators of intravenous immunoglobulin function. CONCLUSIONS: Our results show the differential proteomic profile of serum exosomes of patients with Kawasaki disease before and after intravenous immunoglobulin therapy, such as complement C3, apolipoprotein A-IV, and insulin-like growth factor-binding protein complex acid labile subunit. These results may be useful in the identification of markers for monitoring intravenous immunoglobulin therapy in patients with Kawasaki disease.

PKCα-GSK3ß-NF-κB signaling pathway and the possible involvement of TRIM21 in TRAIL-induced apoptosis.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a highly promising therapeutic agent for cancer treatment, owing to its ability to selectively target tumor cells for cell death while having little effect on most normal cells. However, recent research has found that many cancers, including non-small cell lung cancer (NSCLC), display resistance to TRAIL. Therefore, it is important to elucidate the molecular mechanisms governing the resistance of tumor cells to TRAIL treatment. In this study, we show that GSK3ß antagonized TRAIL-induced apoptosis in H1299 NSCLC cells, and determined that the PKCα isozyme is an upstream regulator of GSK3ß that phosphorylates and inactivates GSK3ß, thereby sensitizing cancer cells to TRAIL-induced apoptosis. Furthermore, we demonstrated that the anti-apoptotic effect of GSK3ß is mediated by the NF-κB pathway, whereas the tripartite motif 21 (TRIM21) was able to inhibit the activation of NF-κB by GSK3ß, and leads to the promotion of cell apoptosis. Taken together, our study further delineated the underpinning mechanism of resistance to TRAIL-induced apoptosis in H1299 cells, and provided new clues for sensitizing NSCLC cells to TRAIL therapy.

14-3-3ζ reduces DNA damage by interacting with and stabilizing proliferating cell nuclear antigen.

Proliferating cell nuclear antigen (PCNA) is a processivity factor of DNA replication which plays critical roles in the regulation of DNA replication and repair. In this study, we show that PCNA interacts directly in vitro and in cells with 14-3-3ζ, an adaptor protein that regulates cell growth and response to DNA damage in eukaryotes. The interaction is mediated by at least two PCNA-binding sites on 14-3-3ζ, one of which is a novel non-canonical PIP (PCNA interacting protein) box. We find that DNA damages induced by UVC irradiation and MMS (methyl methanesulfonate) can enhance both the interaction of these two proteins and their co-localization with chromatin. Functional analyses suggest that 14-3-3ζ stabilizes PCNA possibly by regulating its ubiquitination, which impacts on DNA damage repair and cell viability.

Ser9-phosphorylated GSK3ß induced by 14-3-3ζ actively antagonizes cell apoptosis in a NF-κB dependent manner.

The activity of glycogen synthase kinase beta (GSK3ß) is mainly regulated by its Ser9 phosphorylation. It has been believed for a long time that Ser9 phosphorylation regulates the functions of GSK3ß through inhibition of its kinase activity. In this study, we have confirmed the interaction of Ser9-phosphorylated GSK3ß with 14-3-3ζ by using GST pull-down assays. We show that 14-3-3ζ enhances Ser9 phosphorylation of GSK3ß by PKC. Surprisingly, using a NF-κB luciferase reporter system, we find that Ser9-phosphorylation of GSK3ß promoted by 14-3-3ζ is critical for the activation of NF-κB pathway, which may thwart the pro-apoptotic activity of GSK3ß. Inhibition of either NF-κB or GSK3ß significantly abolishes the anti-apoptotic effect of 14-3-3ζ and Ser9-phosphorylated GSK3ß, suggesting that Ser9-phosphorylated GSK3ß actively antagonizes cell apoptosis in a NF-κB dependent manner.

The highly conserved negatively charged Glu141 and Asp145 of the G-protein-coupled receptor RXFP3 interact with the highly conserved positively charged arginine residues of relaxin-3.

Relaxin-3 is a newly identified insulin/relaxin superfamily peptide that plays a putative role in the regulation of food intake and stress response by activating its cognate G-protein-coupled receptor RXFP3. Relaxin-3 has three highly conserved arginine residues, B12Arg, B16Arg and B26Arg. We speculated that these positively charged arginines may interact with certain negatively charged residues of RXFP3. To test this hypothesis, we first replaced the negatively charged residues in the extracellular domain of RXFP3 with arginine, respectively. Receptor activation assays showed that arginine replacement of Glu141 or Asp145, especially Glu141, significantly decreased the sensitivity of RXFP3 to wild-type relaxin-3. In contrast, arginine replacement of other negatively charged extracellular residues had little effect. Thus, we deduced that Glu141 and Asp145, locating at the extracellular end of the second transmembrane domain, played a critical role in the interaction of RXFP3 with relaxin-3. To identify the ligand residues interacting with the negatively charged EXXXD motif of RXFP3, we replaced the three conserved arginines of relaxin-3 with negatively charged glutamate or aspartate, respectively. The mutant relaxin-3s retained the native structure, but their binding and activation potencies towards wild-type RXFP3 were decreased significantly. The compensatory effects of the mutant relaxin-3s towards mutant RXFP3s suggested two probable interaction pairs during ligand-receptor interaction: Glu141 of RXFP3 interacted with B26Arg of relaxin-3, meanwhile Asp145 of RXFP3 interacted with both B12Arg and B16Arg of relaxin-3. Based on these results, we proposed a relaxin-3/RXFP3 interaction model that shed new light on the interaction mechanism of the relaxin family peptides with their receptors.

A Interacting Model: How TRIM21 Orchestrates with Proteins in Intracellular Immunity.

Tripartite motif-containing protein 21 (TRIM21), identified as both a cytosolic E3 ubiquitin ligase and FcR (Fragment crystallizable receptor), primarily interacts with proteins via its PRY/SPRY domains and promotes their proteasomal degradation to regulate intracellular immunity. But how TRIM21 involves in intracellular immunity still lacks systematical understanding. Herein, it is probed into the TRIM21-related literature and raises an interacting model about how TRIM21 orchestrates proteins in cytosol. In this novel model, TRIM21 generally interacts with miscellaneous protein in intracellular immunity in two ways: For one, TRIM21 solely plays as an E3, ubiquitylating a glut of proteins that contain specific interferon-regulatory factor, nuclear transcription factor kappaB, virus sensors and others, and involving inflammatory responses. For another, TRIM21 serves as both E3 and specific FcR that detects antibody-complexes and facilitates antibody destroying target proteins. Correspondingly delineated as Fc-independent signaling and Fc-dependent signaling in this review, how TRIM21's interactions contribute to intracellular immunity, expecting to provide a systematical understanding of this important protein and invest enlightenment for further research on the pathogenesis of related diseases and its prospective application is elaborated.

Ferroptosis in cancer (Review).

Ferroptosis is a type of programmed cell death depending on iron and reactive oxygen species. This unique cell death process has attracted a great deal of attention in the field of cancer research over the past decade. Research on the association of ferroptosis signal pathways and cancer development indicated that targeting ferroptosis has great potential for cancer therapy. In the present study, the latest research progress of ferroptosis was reviewed, focusing on the relationship between ferroptosis and the development of cancer, in order to further promote the clinical application of ferroptosis in cancer.

[TRIM21 Inhibits the Proliferation and Migration of Lung Adenocarcinoma Cells 
by Interacting with ZSWIM1].

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly morbid and fatal cancer. Despite advancements in modern medical treatment, the 5-year survival rate of patients remains suboptimal. Our previous study revealed that zinc finger SWIM-type containing 1 (ZSWIM1), a novel protein, promotes the proliferation, migration, and invasion of LUAD cells. The aim of this study is to investigate the impact of E3 ubiquitin ligase tripartite motif protein 21 (TRIM21) on ZSWIM1-mediated cell proliferation and migration. METHODS: The interaction and co-localization between TRIM21 and ZSWIM1 were verified using co-immunoprecipitation (Co-IP) and immunofluorescence (IF). The effects of TRIM21 and ZSWIM1 on the proliferation and migration of LUAD cells were assessed through MTT and Transwell assays, respectively. Western blot (WB) analysis was conducted to evaluate the impact of TRIM21 and ZSWIM1 on the expression of epithelial-mesenchymal transition (EMT) markers in LUAD cells. The influence of TRIM21 on the ubiquitination of ZSWIM1 was examined using Co-IP combined with WB. RESULTS: TRIM21 was found to interact and co-localize with ZSWIM1. Overexpression of TRIM21 inhibited the proliferation and migration of LUAD cells. Overexpression of TRIM21 reduced the promoting effect of ZSWIM1 on the proliferation, migration, and invasion of lung adenocarcinoma cells, and reversed the impact of ZSWIM1 on the expression of E-cadherin and Vimentin. Conversely, knockdown of TRIM21 further enhanced the promoting effect of ZSWIM1 on the proliferation and migration of LUAD cells. Mechanistically, we observed that overexpression of TRIM21 significantly enhanced the ubiquitination level of ZSWIM1, leading to a decrease in ZSWIM1 protein expression. CONCLUSIONS: TRIM21 binds to and promotes the ubiquitination of ZSWIM1, resulting in reduced protein expression of ZSWIM1, which leads to the inhibition of ZSWIM1-mediated promotion of proliferation, migration, and invasion in LUAD cells.

TRIAL-based combination therapies in cancers.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows promising therapeutic potential in cancer treatment as it is able to trigger extrinsic apoptotic pathways by binding to the cognate death receptor, causing broad-spectrum apoptosis in cancer cells with negligible toxicity to normal cells. However, the majority of cancers display resistance to TRAIL, limiting its clinical utility. Overcoming resistance to TRAIL therapies remains a challenge in the development of effective anti-cancer strategies. To address the limitations of TRAIL therapy, a viable alternative approach involves combining TRAIL with more potent drugs compared to monotherapy. This combination strategy aims to induce synergistic effects or sensitize drug-resistant cancer cells. This review provides an overview of relevant modalities of TRAIL combination therapy, highlighting different drug classes. The findings demonstrate that combining TRAIL with other agents can effectively counteract resistance observed with TRAIL therapies in cancer. These findings lay a foundation for future advancements in TRAIL-based therapies for treating various cancers.