Objective: Endometrial cancer (EC) remains a significant clinical challenge, particularly for patients with advanced or recurrent disease. This study aims to investigate the effects of Sanguinarine Chloride (S.C), a natural benzophenanthridine alkaloid with broad anti-tumor properties, on EC cell growth and invasion, and to elucidate its underlying molecular mechanisms. Methods: S.C's effects on EC cell viability, proliferation, invasion, and apoptosis were evaluated using CCK-8, EdU, colony formation, 3D matrigel drop assay, FACS and Western blotting (WB). To evaluate its effects on ferroptosis, malondialdehyde (MDA) assay kits, DCFH-DA and the C11 BODIPY581/591 probe, were employed. The molecular mechanisms through which S.C regulates FTO-ACSL4 axis were investigated using plasmid transfection and WB. Additionally, a mouse xenograft model derived from EC cells was established to evaluate the in vivo effects of S.C and its molecular mechanisms, utilizing hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and WB. Results: S.C significantly inhibited EC cell growth and invasion. It induced cell death primarily through ferroptosis, as inhibitors (Ferrostatin-1, Deferoxamine) reversed this effect. S.C downregulated the RNA demethylase FTO, leading to increased ACSL4 expression, enhanced lipid peroxidation, suppression of the NRF2-GPX4 axis, and activated NCOA4-mediated ferritinophagy. Knocking down or pharmacologically inhibiting ACSL4 reduced S.C-induced ferroptosis. Furthermore, in a murine xenograft model, S.C significantly suppressed tumor growth, which was associated with consistent alterations in these ferroptosis-related markers in vivo. Conclusions: Our findings reveal that S.C triggers ferroptosis in EC via the novel FTO-ACSL4 axis, highlighting its potential as a therapeutic agent and identifying the FTO-ACSL4 pathway as a promising target for endometrial cancer treatment.

Prostate cancer (PCa) remains a leading cause of cancer-associated morbidity among men globally. Although enzalutamide (ENZ), a second-generation androgen receptor (AR) antagonist, serves as a mainstay therapy for castration-resistant prostate cancer (CRPC), therapeutic resistance inevitably emerges. This underscores an urgent demand for innovative treatment strategies. CCK-8, colony formation, EdU staining, flow cytometry, Hoechst 33,258 staining, western blotting, proteomics analysis, and senescence-associated β-galactosidase (SA-β-gal) staining were performed to reveal the role and underlying mechanisms of S.C in ENZ-resistant prostate cancer. Target prediction, molecular docking, and cellular thermal shift assay (CETSA) were used to identify the target of S.C. Finally, the impact of S.C in vivo was evaluated using ENZ-resistant xenograft models. Our results showed that S.C effectively suppresses cell viability in ENZ-resistant models through the dual induction of apoptosis and cellular senescence. Database mining, molecular docking, and CETSA identified AR as a putative target of S.C, which was subsequently validated in vivo. S.C treatment significantly inhibited the AR signaling pathway and suppressed tumor growth in ENZ-resistant xenograft models. To our knowledge, this study demonstrates that S.C could be a promising multi-mechanistic agent which can overcome ENZ resistance by targeting AR and inducing two distinct cell death pathways, offering a potential novel therapeutic strategy for CRPC.

Background/Objectives: Chronic glomerulonephritis (CGN) is a progressive chronic kidney disease that can ultimately advance to end-stage renal disease (ESRD). Zhuangyang Bushen Pill (ZYBSW) is a traditional Chinese herbal formulation derived from the Yi ethnic medicine of Yunnan Province, and it has been widely employed in folk practice for the amelioration of chronic nephritis and renal dysfunction. This study was designed to evaluate the therapeutic efficacy of ZYBSW against CGN and to provide preliminary insights into its underlying mechanisms of action. Methods: The nephropathy model was induced in mice by tail vein injection of ADR (10 mg/kg). Renal function was evaluated by measuring relevant biochemical parameters, and renal histopathological alterations were examined using HE staining. Chemical constituents of ZYBSW were analyzed by LC-MS/MS. Its mechanisms of action were investigated using network pharmacology, WGCNA, molecular docking, multiplex immunofluorescence, and Western blotting. Results: ZYBSW significantly reduced ACR by 88.9%, SCr by 56.4%, and BUN by 30.4%, increased ALB by 32.4%, and alleviated renal histopathological damage (all p < 0.01). LC-MS/MS analysis identified 419 chemical constituents in ZYBSW. Network pharmacology, WGCNA, and molecular docking experiments identified EGFR and DUSP1 as potential targets, and indicated the MAPK pathway as a key pathway. Mechanistic studies revealed that ZYBSW significantly inhibited EGFR expression in renal tissue, enhanced DUSP1 expression, and reduced the phosphorylation levels of ERK, JNK, and p38. Conclusions: This study reveals ZYBSW can effectively alleviate CGN, with EGFR and DUSP1 as likely therapeutic targets, and its mechanism of action primarily involves regulating the MAPK signaling pathway.

TAK-901 suppresses bladder cancer cell growth in vitro, related to Figure 2

Bisphenol A (BPA) is a widely used industrial chemical present in numerous consumer products such as plastics, epoxy resins, and thermal paper. Growing evidence suggests that BPA may pose potential health risks, particularly in relation to carcinogenesis. In this study, we investigated the toxic effects and carcinogenic role of BPA using two bladder cancer cell lines, T24 and UMUC. Our results show that BPA influences cell viability and migration in a dose-dependent manner. At low concentrations, BPA significantly promoted cell growth and cell migration in both T24 and UMUC cells, whereas higher concentrations suppressed cell growth. Proteomic and transcriptomic analyses further revealed substantial changes in protein and gene expression profiles following BPA exposure. Bioinformatics analysis suggested that BPA may modulate bladder cancer cell behavior through the MAPK signaling and inflammatory response pathways. Together, these findings offer important insights into the molecular mechanisms of BPA-induced cellular alterations, with potential implications for developing more targeted and effective therapeutic strategies for cancer. Future studies should focus on further elucidating the signaling pathways affected by BPA, exploring its potential synergistic or antagonistic interactions with other environmental factors, and validating these results through in vivo models.

Bladder cancer is the most prevalent malignancy of the urinary tract, characterized by an unfavorable prognosis, elevated rates of recurrence, and a lack of targeted therapeutic approaches. In this research, we evaluated the efficacy of TAK-901, a specific inhibitor targeting Aurora kinase, and elucidated the anticancer mechanisms in bladder cancer. TAK-901 exhibited a dose-dependent inhibition of proliferation, colony formation, and migration, as well as the induction of apoptosis in T24 and UMUC-3 cells. Additionally, bladder cancer cells underwent cell-cycle arrest at the G2-M-phase when exposed to TAK-901. Mechanistic studies revealed that the targeted inhibition of epidermal growth factor receptor (EGFR) by TAK-901 affected AKT and forkhead box class O3a (FOXO3a) phosphorylation, leading to the activation of FOXO-dependent transcriptional activity, which subsequently triggered apoptotic pathways by inducing BIM expression. Furthermore, our study demonstrated that TAK-901 attenuated tumor growth in the UMUC-3-luciferase xenograft model and significantly reduced Ki-67 expression in tumor tissues. Finally, we propose a novel treatment strategy involving the synergistic inhibition of bladder cancer cell growth by combining TAK-901 with afatinib. Our research strongly suggests that Aurora A and Aurora B are promising epigenetic therapeutic targets in bladder cancer. Furthermore, TAK-901 can function as a targeted kinase inhibitor and EGFR inhibitor for the treatment of bladder cancer by activating the FOXO signaling pathway, which induces apoptosis in bladder cancer cells.

Bladder cancer cell viability and migration were assessed using CCK-8 and wound healing assays following Sanguinarine Chloride (SANC) treatment. Molecular targets and pathways were predicted through network pharmacology and proteomic analysis. Reactive oxygen species(ROS) and glutathione(GSH) levels were measured to evaluate redox balance. The interaction between SANC and EGFR was validated via molecular docking and surface plasmon resonance(SPR). Protein expression was analyzed using Western blotting and immunofluorescence, and a xenograft mouse model was employed to assess in vivo antitumor efficacy. SANC significantly inhibited bladder cancer cell proliferation, colony formation, and migration. Mechanistically, SANC bound to EGFR and downregulated the PI3K/AKT/FOXO3a signaling pathway, leading to cell cycle arrest and apoptosis. SANC also increased ROS levels and GSH contributing to redox imbalance and further suppression of EGFR activity. In vivo, SANC markedly reduced tumor growth without obvious systemic toxicity. Collectively, SANC exerts potent anti-tumor effects against bladder cancer by directly targeting EGFR, inhibiting the PI3K/AKT/FOXO3a signaling axis, and disrupting redox homeostasis. These findings support the therapeutic potential of SANC as a novel EGFR-targeted agent for bladder cancer treatment.

Prostate cancer is a major global health challenge, characterized by high morbidity and mortality rates. Traditional treatment options, including androgen deprivation therapy and chemotherapy, often lead to drug resistance. In recent years, natural compounds have garnered attention for their potential therapeutic effects. Evodiamine, a bioactive alkaloid from Evodia rutaecarpa, has demonstrated promising anti-cancer properties in various malignancies, including oral squamous cell carcinoma, breast, colorectal, and ovarian cancers. This study explores the efficacy of evodiamine in prostate cancer cells and investigates the mechanisms underlying evodiamine-induced cell death. To investigate the effects of evodiamine on prostate cancer cells, various cell lines, including both castration-sensitive and castration-resistant variants, were treated with different concentrations of evodiamine for various durations. Cell viability, proliferation, invasion ability, and colony formation were assessed using the CCK8 assay, EdU assay, 3D matrigel drop invasion assay, and colony formation assay, respectively. The effects of evodiamine on apoptosis were analyzed using FACS, Hoechst staining, and Western blot. To evaluate its effects on ferroptosis, malondialdehyde (MDA) and glutathione (GSH) assay kits, as well as DCFH-DA and the lipid peroxidation sensor BODIPY™ 581/501 C11 fluorescent probes, were employed. The molecular mechanisms through which evodiamine regulates GPX4 protein instability were investigated using Western blot and TRIM26 ectopic expression. Additionally, a mouse xenograft model derived from DU145 cells was established to evaluate the in vivo effects of evodiamine and its molecular mechanisms, utilizing hematoxylin and eosin (H E) staining, immunohistochemistry (IHC), and Western blot analysis. Evodiamine significantly suppressed cell viability, proliferation, invasion, and colony formation in prostate cancer cells. Importantly, evodiamine-induced cell death in the PC3 and DU145 cell lines was independent of apoptosis pathway. Instead, evodiamine increased reactive oxygen species (ROS) production, lipid ROS levels and MDA levels, while decreasing GSH levels, indicating the induction of ferroptosis. The key role of ROS in evodiamine-induced ferroptosis was further confirmed by the partial reversal of cell death upon treatment with the ROS scavenger N-acetylcysteine (NAC). Mechanistically, evodiamine induced ferroptosis by destabilizing GPX4 protein in a TRIM26-dependent manner. Moreover, in vivo studies demonstrated that evodiamine significantly inhibited tumor growth and induced ferroptosis in tumor cells, highlighting its therapeutic potential. This study demonstrates that evodiamine exerts potent antitumor effects against prostate cancer through inhibiting TRIM26-mediated stabilization of GPX4 protein and triggering ferroptosis. These findings suggest that evodiamine, a natural product derived from traditional Chinese medicine, could be a promising therapeutic agent for prostate cancer.

Chemotherapy remains the main treatment for muscle-invasive bladder cancer (BLCA) despite drug resistance and lack of target drugs greatly limiting long-term survival of patients. Thus, novel and effective drugs specific to BLCA are required to aid in its treatment and improve patient survival. In the present study, we found that the compound Ro-31-8220, a pan-protein kinase C inhibitor, displays potent anti-bladder cancer efficacy in vitro and in vivo. Ro-31-8220 treatment suppressed bladder cancer cell migration and invasion and also induced cell apoptosis in a dose-dependent manner. Proteomic analysis showed that Ro-31-8220 treatment altered the expression of numerous proteins and KEGG enrichment analysis demonstrated that multiple signal pathways are regulated by Ro-31-8220, including autophagy. To further validate these results, we carried out western blotting, GFP-LC3 fusion protein and transmission electron microscopy analyses, all of which demonstrated that Ro-31-8220 induced bladder cancer cell autophagy. Blockade of autophagy with chloroquine, an autophagy inhibitor, attenuated Ro-31-8220 induced bladder cancer cell death. In a bladder cancer xenograft tumor growth mice model, we showed that intraperitoneal injection of Ro-31-8220 significantly decreased tumor size and tumor weight compared to the control group, suggesting an in vivo tumor suppression ability of Ro-31-8220 through activation of autophagy. These results suggest that Ro-31-8220 may be a novel promising candidate drug for bladder cancer therapy. Further studies, including clinical trials, are required to validate these results.

Ovarian cancer is characterized by poor specificity and unfavorable prognosis. Therefore, exploring new mechanisms of ovarian cancer development, identifying specific new targets, and developing effective therapeutic drugs based on these new targets have become the focus of current research. This study collected clinical case tissues from high-grade serous ovarian cancer (HGSC) patients and found that the expression of RecQ-like helicase 4 (RECQL4) was positively correlated with the malignancy of ovarian cancer but negatively correlated with its prognosis. From the chemical library of traditional Chinese medicine and ethnic medicines established by our research group in Guizhou, we screened out an effective target, a fluorinated tanshinone analogue (TC12-1), which can effectively inhibit and bind to RECQL4. In vitro experiments showed that TC12-1 induced apoptosis and inhibited cancer cell invasion and metastasis. Additionally, TC12-1 can induce DNA damage, enhancing replication fork stress and blocking the cell cycle at the S phase in cancer cells. The compound effectively inhibited tumor growth and metastasis in subcutaneous tumor models and in orthotopic ovarian cancer mouse models, showing no significant toxicity to vital organs in tumor animal models. The molecular mechanism of TC12-1 targeting RECQL4 in anti-ovarian epithelial cell carcinoma involves the regulation of key genes such as γ-H2AX, PRPA32, ATM, RAD50, CHK2, P53, P21, Bax, Cyclin E, and CDC2, thereby affecting the cell cycle and DNA replication signaling pathways. The results provide theoretical support for developing specific ovarian cancer therapeutic drugs using RECQL4 as a new target.

Given the critical necessity for the development of more potent anti-cancer drugs, a series of novel compounds incorporating trifluoromethyl groups within the privileged 2-anilinoquinoline scaffold was designed, synthesized, and subjected to biological evaluation through a pharmacophore hybridization strategy. Upon evaluating the in vitro anti-cancer characteristics of the target compounds, it became clear that compound 8b, which contains a (4-(piperazin-1-yl)phenyl)amino substitution at the 2-position of the quinoline skeleton, displayed superior efficacy against four cancer cell lines by inducing apoptosis and cell cycle arrest. Following research conducted in a PC3 xenograft mouse model, it was found that compound 8b exhibited significant anti-cancer efficacy while demonstrating minimal toxicity. Additionally, the analysis of a 217-kinase panel pinpointed SGK1 as a potential target for this compound class with anti-cancer capabilities. This finding was further verified through molecular docking analysis and cellular thermal shift assays. To conclude, our results emphasize that compound 8b can be used as a lead compound for the development of anti-cancer drugs that target SGK1.

Acute kidney injury (AKI) is a common side effect of the chemotherapy agent cisplatin, and ferroptosis serves as the primary mechanism underlying cell death in renal tubular epithelium in such cases. Salvianolic acid B (SAB), a compound derived from Salvia miltiorrhiza, has demonstrated promising anti-inflammatory and antioxidant properties. However, its impact on ferroptosis in the context of AKI remains to be fully explored. In this study, we utilized cisplatin-induced and folic acid-induced AKI models to investigate the protective mechanisms of SAB on renal tissue and tubular epithelial cell injury. The impact of SAB on renal cell ferroptosis was thoroughly examined and confirmed in both AKI models. To predict the potential mechanism through which SAB regulates ferroptosis, we employed an online target prediction database and subsequently verified the specific target proteins involved. Furthermore, we used drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking techniques to assess the binding capacity of SAB to the target protein. Our results reveal that SAB alleviated cisplatin- and folic acid-induced renal dysfunction in vivo and improved cisplatin-induced HK-2 cell injury. Mechanistically, SAB targeted and bound to PRDX5, enhancing its redox activity, which in turn potentiated the inhibitory effect of SLC7A11 and GPX4 on cisplatin-induced ferroptosis. Silencing PRDX5 in HK-2 cells could partially abrogate the protective effect of SAB. These results provide strong evidence for the potential of SAB in the treatment of AKI.

The development of cisplatin resistance often results in a grim prognosis in advanced or recurrent bladder cancer. However, effective treatment strategies for cisplatin resistance have not been well established. Herein, we found that overactivation of SRC is associated with cisplatin-resistance. SRC activates hexokinase2 which up-regulates glycolysis and especially the pentose phosphate pathway that leading to increased nucleotide synthesis and NADPH production which can neutralize reactive oxygen species (ROS) induced by cisplatin, thereby protecting bladder cancer cells from cisplatin-induced DNA damage. This phenomenon was effectively reversed by knockout of SRC and inhibition of SRC activity by the SRC inhibitor, eCF506. Moreover, we constructed Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) from cisplatin-resistant bladder cancer patient. eCF506 exhibited excellent anti-tumor effects and effectively enhanced cisplatin-sensitivity. Altogether, our findings demonstrate that targeting SRC is a promising approach to overcome cisplatin-resistance in bladder cancer, and providing new insights for combination therapy in bladder cancer. SRC-mediated reprogramming of energy metabolism towards glycolysis and the pentose phosphate pathway contributes to cisplatin resistance in bladder cancer.

Prostate cancer is the most common cancer and remains a leading cause of cancer-related deaths among men worldwide. Androgen deprivation therapy continues to be the cornerstone of treatment for prostate cancer. However, the efficacy of this treatments is often limited, leading to the emergence of drug resistance and tumor recurrence. TAK-901, an inhibitor of Aurora kinase B, has been shown to inhibit tumor growth both in vitro and in vivo models. To date, the effect of TAK-901 on prostate cancer and the underlying mechanism remain unknown. In this study, we found that TAK-901 could inhibit proliferation, colony formation and migration, while also inducing apoptosis in prostate cancer cells. We further demonstrated that TAK-901 activates the CHK1 signaling pathway, leading to G2/M-phase arrest in these cells. Additionally, we identified EPHA2 as a novel therapeutic target of TAK-901. By mutating the binding sites between EPHA2 and TAK-901, we discovered that these mutations could reverse the anti-proliferative effects of TAK-901 in prostate cancer models. Our study is the first to reveal that TAK-901 induces apoptosis in prostate cancer cells and inhibits cell growth by targeting EPHA2. These findings provide valuable insights into the underlying mechanisms of TAK-901 and may develop its therapeutic applications in prostate cancer.

Prostate cancer is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC). CRPC metastasis is the main reason for its high mortality rate. At present, it lacks effective treatment for patients with CRPC. Raltitrexed (RTX) has been shown to be effective in the treatment of colorectal cancer. However, the effect of RTX on prostate cancer and the underlying mechanism remain unknown. In the current study, we found that RTX could dose-dependently inhibit proliferation, migration, colony formation and induce apoptosis in DU145 and PC-3 cells. RTX also increased ROS generation in prostate cancer cells. Pretreatment with N-acetyl-L-cysteine (NAC) significantly prevented RTX-induced cell apoptosis and endoplasmic reticulum (ER) stress signaling activation in prostate cancer cells. Additionally, we found RTX-induced ROS generation and ER stress activation depended on the expression of heat shock protein family A member 8 (HSPA8). Over-expression of HSPA8 could alleviate RTX-induced cell apoptosis, ROS generation and ER stress signaling activation. Finally, our study also showed that RTX attenuated the tumor growth of prostate cancer in the DU145 xenograft model and significantly downregulated HSPA8 expression and activated ER stress signaling pathway in tumor tissues. Our study is the first to reveal that RTX induces prostate cancer cells apoptosis through inhibiting the expression of HSPA8 and further inducing ROS-mediated ER stress pathway action. This study suggests that RTX may be a novel promising candidate drug for prostate cancer therapy.

Background Sanguinarine chloride (S.C) is a benzophenanthrine alkaloid derived from the root of sanguinaria canadensis and other poppy-fumaria species. Studies have reported that S.C exhibits antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects, which contribute to its anti-cancer properties. Recent studies suggested that the antitumor effect of S.C through inducing ferroptosis in some cancers. Nevertheless, the precise mechanism underlying the regulation of ferroptosis by S.C remains poorly understood. Methods A small molecule library was constructed based on FDA and CFDA approved small molecular drugs. CCK-8 assay was applied to evaluate the effects of the small molecule compound on tumor cell viability. Prostate cancer cells were treated with S.C and then the cell viability and migration ability were assessed using CCK8, colony formation and wound healing assay. Reactive oxygen species (ROS) and iron accumulation were quantified through flow cytometry analysis. The levels of malondialdehyde (MDA) and total glutathione (GSH) were measured using commercially available kits. RNA-seq analysis was performed to identify differentially expressed genes (DEGs) among the treatment groups. Western blotting and qPCR were utilized to investigate the expression of relevant proteins and genes. In vivo experiments employed a xenograft mice model to evaluate the anti-cancer efficacy of S.C. Results Our study demonstrated that S.C effectively inhibited the viability of various prostate cancer cells. Notably, S.C exhibited the ability to enhance the cytotoxicity of docetaxel in DU145 cells. We found that S.C-induced cell death partially relied on the induction of ferroptosis, which was mediated through up-regulation of HMOX1 protein. Additionally, our investigation revealed that S.C treatment decreased the stability of BACH1 protein, which contributed to HMOX1expression. We further identified that S.C-induced ROS caused BACH1 instability by suppressing USP47expression. Moreover, In DU145 xenograft model, we found S.C significantly inhibited prostate cancer growth, highlighting its potential as a therapeutic strategy. Collectively, these findings provide evidence that S.C could induce regulated cell death (RCD) in prostate cancer cells and effectively inhibit tumor growth via triggering ferroptosis. This study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting ROS/USP47/BACH1/HMOX1 axis. Conclusion This study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting the ROS/USP47/BACH1/HMOX1 axis. These findings offer novel insights into the underlying mechanism by which S.C inhibits the progression of prostate cancer. Furthermore, leveraging the potential of S.C in targeting ferroptosis may present a new therapeutic opportunity for prostate cancer. This study found that S.C induces ferroptosis by targeting the ROS/USP47/BACH1/HMOX1 axis in prostate cancer cells. Graphical Abstract

Background: SPRR1B, a member of the small proline-rich protein family, is implicated in various epithelial cancers as a potential oncogene linked to tumour growth and poor survival outcomes. However, its role in urothelial bladder carcinoma (UBC) remains to be fully elucidated. Methods: Transcriptional profiling data from The Cancer Genome Atlas grouped UBC samples in accordance with SPRR1B expression. Bioinformatic analysis was conducted to evaluate whether SPRR1B is a prognostic factor and a survival factor in UBC. Gene set enrichment analysis (GSEA) was performed to study immune cells and pathways. Reverse transcription quantitative real-time polymerase chain reaction detected gene expression. Immunohistochemistry assessed protein expression. Spearman correlation test analysed the correlation between SPRR1B and the protein p53. Results: The bioinformatics results indicated that the expression level of SPRR1B in UBC tissues was significantly increased compared with that in normal bladder tissues, correlating with clinical characteristics. A high expression predicted poor prognosis and survival. Univariate Cox statistics showed that a high expression level of SPRR1B was correlated with UBC patients having poor overall survival (OS) (p < 0.05). In addition, on the basis of the multivariate Cox analysis, SPRR1B expression was independently correlated with OS (p = 0.005). GSEA analysis revealed enrichment in the p53, apoptosis, and cell cycle signalling pathways, and an association with B cells, lymphocytes, and natural killer cells. In addition, SPRR1B was found to be associated with immune infiltration based on the analysis of immune cell infiltration. Performing corresponding verification on a small number of tissues collected from bladder cancer patients revealed that the expression of this protein was negatively correlated with the expression of p53. Conclusions: SPRR1B overexpression predicts poor UBC outcomes, suggesting its role as a prognostic marker and therapeutic target. Further research is necessary to elucidate its role in UBC progression.

Bladder cancer (BC) is the most common cancer of the urinary tract, with poor survival, high recurrence rates, and lacking of targeted drugs. In this study, we constructed a library to screen compounds inhibiting bladder cancer cells growth. Among them, SRT1720 was identified to inhibit bladder cancer cell proliferation in vitro and in vivo. SRT1720 treatment also suppressed bladder cancer cells migration, invasion and induced apoptosis. Mechanism studies shown that SRT1720 promoted autophagosomes accumulation by inducing early-stage autophagy but disturbed the late-stage of autophagy by blocking fusion of autophagosomes and lysosomes. SRT1720 appears to induce autophagy related proteins expression and alter autophagy-related proteins acetylation to impede the autophagy flux. LAMP2, an important lysosomal associated membrane protein, may mediate SRT1720-inhibited autophagy flux as SRT1720 treatment significantly deacetylated LAMP2 which may influence its activity. Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment.

目的 探讨泛素结合酶E2C(UBE2C)在肾透明细胞癌(KIRC)中的表达模式、临床预后价值以及调节KIRC的分子机制.方法 通过肿瘤基因组图谱数据库(TCGA)和人类蛋白质表达图谱数据库(HPA)分析UBE2C基因在KIRC组织和正常组织中的表达差异.结合KIRC患者的临床信息,利用单因素及多因素Cox回归模型分析UBE2C基因在KIRC患者中的预后价值.通过基因富集分析(GSEA)了解UBE2C基因调控KIRC的分子机制.计算KIRC患者中的浸润免疫细胞含量,并评估UBE2C基因表达水平与免疫细胞浸润含量的相关性.结果 KIRC组织中的UBE2C基因和蛋白表达水平均高于正常肾组织(P<0.05).KIRC组织中UBE2C表达与肿瘤位置、组织学分级、病理分期及TNM分期有关(P<0.05).单因素及多因素Cox回归分析结果显示,UBE2C可作为预测KIRC患者总生存期(OS)的独立预后因素(P<0.05).GSEA结果表明,UBE2C可能参与调节细胞因子-细胞因子受体相互作用、细胞周期检查点、ECM糖蛋白等多条信号通路.UBE2C基因表达水平与KIRC肿瘤微环境中Treg细胞、T细胞、Th17细胞、B细胞、CD8+T细胞和巨噬细胞浸润等显著相关.UBE2C同免疫检查点分子PDCD1(PD1)、CTLA4、CD27、LAG3等表达水平也显著相关.结论 UBE2C可作为KIRC患者的一个风险预后因子,同时UBE2C可能作为KIRC治疗的潜在靶点.