ACAT1 promotes proliferation and metastasis of bladder cancer via AKT/GSK3ß/c-Myc signaling pathway.

Acetyl-CoA acetyltransferase 1 (ACAT1) plays a significant role in the regulation of gene expression and tumorigenesis. However, the biological role of ACAT1 in bladder cancer (BLCA) has yet to be elucidated. This research aimed to elucidate the bioinformatics features and biological functions of ACAT1 in BLCA. Here, we demonstrate that ACAT1 is elevated in BLCA tissues and is correlated with specific clinicopathological features and an unfavorable prognosis for survival in BLCA patients. ACAT1 was identified as an independent risk factor in BLCA. Phenotypically, both in vitro and in vivo, ACAT1 knockdown suppressed BLCA cell proliferation and migration, while ACAT1 overexpression had the opposite effect. Mechanistic assays revealed that ACAT1 enhances BLCA cell proliferation and metastasis through the AKT/GSK3ß/c-Myc signaling pathway by modulating the cell cycle and EMT. Taken together, the results of our study reveal that ACAT1 is an oncogenic driver in BLCA that enhances tumor proliferation and metastasis, indicating its potential as a diagnostic and therapeutic target for this disease.

Causal association of smoking, blood lipids, and bladder cancer: Insights from a multivariable and mediation mendelian randomization investigation.

We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.

Elafibranor emerged as a potential chemotherapeutic drug for non-muscle invasive bladder cancer.

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 µM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.

Pectolinarigenin inhibits bladder urothelial carcinoma cell proliferation by regulating DNA damage/autophagy pathways.

Pectolinarigenin (PEC), an active compound isolated from traditional herbal medicine, has shown potential anti-tumor properties against various types of cancer cells. However, its mechanism of action in bladder cancer (BLCA), which is one of the fatal human carcinomas, remains unexplored. In this study, we first revealed that PEC, as a potential DNA topoisomerase II alpha (TOP2A) poison, can target TOP2A and cause significant DNA damage. PEC induced G2/M phase cell cycle arrest via p53 pathway. Simultaneously, PEC can perform its unique function by inhibiting the late autophagic flux. The blocking of autophagy caused proliferation inhibition of BLCA and further enhanced the DNA damage effect of PEC. In addition, we proved that PEC could intensify the cytotoxic effect of gemcitabine (GEM) on BLCA cells in vivo and in vitro. Summarily, we first systematically revealed that PEC had great potential as a novel TOP2A poison and an inhibitor of late autophagic flux in treating BLCA.

Melatonin inhibits bladder tumorigenesis by suppressing PPARγ/ENO1-mediated glycolysis.

Melatonin is a well-known natural hormone, which shows a potential anticancer effect in many human cancers. Bladder cancer (BLCA) is one of the most malignant human cancers in the world. Chemoresistance is an increasingly prominent phenomenon that presents an obstacle to the clinical treatment of BLCA. There is an urgent need to investigate novel drugs to improve the current clinical status. In our study, we comprehensively explored the inhibitory effect of melatonin on BLCA and found that it could suppress glycolysis process. Moreover, we discovered that ENO1, a glycolytic enzyme involved in the ninth step of glycolysis, was the downstream effector of melatonin and could be a predictive biomarker of BLCA. We also proved that enhanced glycolysis simulated by adding exogenous pyruvate could induce gemcitabine resistance, and melatonin treatment or silencing of ENO1 could intensify the cytotoxic effect of gemcitabine on BLCA cells. Excessive accumulation of reactive oxygen species (ROS) mediated the inhibitory effect of melatonin on BLCA cells. Additionally, we uncovered that PPARγ was a novel upstream regulator of ENO1, which mediated the downregulation of ENO1 caused by melatonin. Our study offers a fresh perspective on the anticancer effect of melatonin and encourages further studies on clinical chemoresistance.

[Effects of let-7a on proliferation, osteogenic differentiation and apoptosis of human dental pulp stem cells].

PURPOSE: To study the effect and possible mechanism of let-7a on proliferation, differentiation and apoptosis of human dental pulp stem cell (hDPSCs). METHODS: The cells were divided into four groups: overexpression control (let-7a control/let-7a agomir control), overexpression let-7a (let-7a mimics/let-7a agomir), knockdown let-7a control (let-7a inhibitor control) and knockdown let-7a (let-7a inhibitor). Cell counting kit-8 assay(CCK-8) was used to detect the proliferation of cells at 24 hours, 48 hours and 72 hours after transfection. Calcified nodules were detected by Alizarin red staining. The protein expression of alkaline phosphatase (ALP), osteopontin (OPN), 4E-binding protein 1 (4EBP1), p-4EBP1, mammalian target of rapamycin (mTOR) and p-mTOR were detected by Western blot. Annexin V-APC/7-AAD cell apoptosis detection kit was used to detect the level of apoptosis after transfection. Statistical analysis was performed using GraphPad Prism 5.0 software. RESULTS: Let-7a inhibited proliferation of hDPSCs and promoted odontoblast differentiation and apoptosis. Let-7a down-regulated the expression of 4EBP1, p-4EBP1, mTOR and p-mTOR. CONCLUSIONS: Let-7a may inhibit proliferation of hDPSCs and promote their differentiation and apoptosis by inhibiting mTOR-4EBP1 molecular pathway.