Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells. Mechanistically, ASPP2 inhibits autophagy through regulating BECN1 transcription and formation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) complex. Firstly, ASPP2 inhibits p65/RelA-induced transcription of BECN1, directly by an ASPP2-p65/RelA-IκBα complex which inhibits phosphorylation of IκBα and the translocation of p65/RelA into the nucleus. Secondly, ASPP2 binds to BECN1, leading to decreased binding of PIK3C3 and UV radiation resistance-associated gene (UVRAG), and increased binding of Rubicon in PIK3C3 complex. Downregulation of ASPP2 enhances the pro-survival and chemoresistant property via autophagy in HCC cells in vitro and in vivo. Decreased ASPP2 expression was associated with increased BECN1 and poor survival in HCC patients. Therefore, ASPP2 is a key regulator of BECN1-dependent autophagy, and decreased ASPP2 may contribute to tumor progression and chemoresistance via promoting autophagy.
Abstract The tumor margin as the invasive front has been proven to be closely related to the progression and metastasis of oral squamous cell carcinoma (OSCC). However, how tumor cells in the marginal region obtain the extra energy needed for tumor progression is still unknown. Here, we used spatial metabolomics and the spatial transcriptome to identify enhanced energy metabolism in the tumor margin of OSCC and identified that the downregulation of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD) in tumor cells mediated this process. The absence of RRAD enhanced the ingestion of glucose and malignant behaviors of tumor cells both in vivo and in vitro. Mechanically, the downregulation of RRAD promoted the internal flow of Ca 2+ and elevated its concentration in the nucleus, which resulted in the activation of the CAMKIV-CREB1 axis to induce the transcription of the glucose transporter GLUT3. GLUT inhibitor-1, as an inhibitor of GLUT3, could suppress this vigorous energy metabolism and malignant behaviors caused by the downregulation of RRAD. Taken together, our study revealed that enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of OSCC and proved that GLUT3 is a potential target for future treatment of OSCC.
Objective
To synthesize N- (5-nitroindazole-3-formyl) tyrosine sodium and investigate its hypoxic radiosensitizing effect and biodistribution.
Method
Synthesized the target compound (N- (5-nitroindazole-3-formyl) tyrosine sodium) using condensing agents, and investigated its radiosensitization under hypoxia using H22 xenograft models and its biodistribution using radioactive iodine labeling.
Results
The synthesis and structure of the target compound were confirmed. Xenograft models showed that it had a certain radiosensitizing activity and the mean value of sensitization enhancement ratio was 1.5. Biodistribution experiment revealed that it had a good distribution manner, the distribution ratios of tumor to the nervous system and muscle were both greater than 5.
Conclusion
N- (5-nitroindazole-3-formyl) tyrosine sodium had good radiosensitizing activity and biodistribution manner, and it was worthy of further study.
Key words:
N- (5-nitroindazole-3-formyl) tyrosine sodium; Neoplasms; hypoxic radiosensitization; biodistribution
Tumor metabolism characterized by aerobic glycolysis makes the Warburg effect a unique target for tumor therapy. Recent studies have found that glycogen branching enzyme 1 (GBE1) is involved in cancer progression. However, the study of GBE1 in gliomas is limited. We determined by bioinformatics analysis that GBE1 expression is elevated in gliomas and correlates with poor prognoses. In vitro experiments showed that GBE1 knockdown slows glioma cell proliferation, inhibits multiple biological behaviors, and alters glioma cell glycolytic capacity. Furthermore, GBE1 knockdown resulted in the inhibition of the NF-κB pathway as well as elevated expression of fructose-bisphosphatase 1 (FBP1). Further knockdown of elevated FBP1 reversed the inhibitory effect of GBE1 knockdown, restoring glycolytic reserve capacity. Furthermore, GBE1 knockdown suppressed xenograft tumor formation in vivo and conferred a significant survival benefit. Collectively, GBE1 reduces FBP1 expression through the NF-κB pathway, shifting the glucose metabolism pattern of glioma cells to glycolysis and enhancing the Warburg effect to drive glioma progression. These results suggest that GBE1 can be a novel target for glioma in metabolic therapy.
5-Fluorouracil (5-Fu) is one of the basic drugs in colorectal cancer (CRC) chemotherapy, and its efficacy is mainly limited by the acquisition of drug resistance. However, the underlying mechanisms remain unclear. In this study, hypoxia inducible factor 1α (HIF1α) was screened for high expression in 5-Fu resistant HCT115 cells, which displayed epithelial-mesenchymal transition (EMT) phenotype. Suppression of HIF1α reversed EMT phenotype, reduced glucose transporter 1 (Glut1) expression, a key molecule mediated drug resistance. Moreover, we unveiled that vascular endothelial growth factor (VEGF) was regulated by HIF1α and mediated HIF1α-maintained malignant phenotype of 5-Fu resistant cells. Further studies verified that AKT/GSK3β signaling was activated in resistant cells and controlled HIF1α expression. Interestingly, we demonstrated that VEGF could feedback up-regulate HIF1α via AKT/GSK3β signaling. Clinically, HIF1α and VEGF were high expressed and associated with survival and prognosis in CRC patients. In conclusion, our findings proposed that HIF1α/VEGF feedback loop contributed to 5-Fu resistance, which might be potential therapeutic targets.
Objective To improve the reliability of experimental outcome in radio-sensitive drug research by improving the animal model of locally irradiated tumor.Methods Liver cancer cells H22 were implanted into legs and insteps subcutaneously in mice,respectively,and made them grow into solid tumors.Then the tumors were treated with the γ ray of 137Cs at the dosage of 5 Gy.Measured length,width and height of tumors once per day,and calculated volume of tumors,observed for 24 days.Results Volume and weight of the irradiated tumor inoculated into legs were no obvious difference (t=0.55、0.70,both P＞0.05).But volume and weight of the irradiated tumors inoculated subcutaneously into insteps of the tested mice were obviously lower than that of control mice (t=2.25,P＜0.05 in volume; t=3.14,P＜0.01 in weight).Conclusion The insteps subcutaneous approach of tumors in mice is a more simple,convenient and practicable operation,and will make the testing result more accurate and reliabe.
Key words:
Liver neoplasms; Radiation injuries, experimental; Models, animal
Porcine liver extract has been shown to be effective in the clinical treatment of severe hepatitis. The aim of the present study was to study its antifibrotic as well as immune regulatory effect in vitro. Hepatocytes, hepatic stellate cells (HSCs), hepatoma cell line (HepG2) and human peripheral blood mononuclear cells (PMNCs) were studied with respect to proliferation, extracellular matrix production and apoptotic activities by proliferation assay, radioimmunoassay, gene transfection, reporter gene analysis and flow cytometry, respectively. A strong stimulatory proliferation effect was observed in hepatocytes, and an inhibitory effect was found in HSCs. Hyaluronic acid (HA) production and reporter gene activities driven by various α1(I) procollagen gene promoters in HSC-T6 were significantly decreased after treatment with the extract. Fluo-Anexin V binding apoptotic HepG2 cells were more prominent in the presence of 60 μg/ml extract. More CD4+/CD69+ positive T lymphocytes existed in the presence of the extract. Porcine liver extract is effective for antifibrogenesis via hepatocyte regeneration, HSC and hepatoma cell inhibition in vitro. The elevation of active T lymphocytes is helpful for immune surveillance. Fine mapping of the extract is necessary in order to get definite molecules which are essential in all described functions.
The utilization of biodegradable magnesium (Mg) alloys in the fabrication of temporary non-vascular stents is an innovative trend in biomedical engineering. However, the heterogeneous degradation profiles of these biomaterials, together with potential bacterial colonization that could precipitate infectious or stenotic complications, are critical obstacles precluding their widespread clinical application. In pursuit of overcoming these limitations, this study applies the principles of biomimicry, particularly the hydrophobic and anti-fouling characteristics of lotus leaves, to pioneer the creation of nanocomposite coatings. These coatings integrate poly-trimethylene carbonate (PTMC) with covalent organic frameworks (COFs), to modify the stent's surface property. The strategic design of the coating's topography, porosity, and self-polishing capabilities collectively aims to decelerate degradation processes and minimize biological adhesion. The protective qualities of the coatings were substantiated through rigorous testing in both in vitro dynamic bile tests and in vivo New Zealand rabbit choledochal models. Empirical findings from these trials confirmed that the implementation of COF-based nanocomposite coatings robustly fortifies Mg implantations, conferring heightened resistance to both biocorrosion and biofouling as well as improved biocompatibility within bodily environments. The outcomes of this research elucidate a comprehensive framework for the multifaceted strategies against stent corrosion and fouling, thereby charting a visionary pathway toward the systematic conception of a new class of reliable COF-derived surface modifications poised to amplify the efficacy of Mg-based stents. STATEMENT OF SIGNIFICANCE: Biodegradable magnesium (Mg) alloys are widely utilized in temporary stents, though their rapid degradation and susceptibility to bacterial infection pose significant challenges. Our research has developed a nanocomposite coating inspired by the lotus, integrating poly-trimethylene carbonate with covalent organic frameworks (COF). The coating achieved self-polishing property and optimal surface energy on the Mg substrate, which decelerates stent degradation and reduces biofilm formation. Comprehensive evaluations utilizing dynamic bile simulations and implantation in New Zealand rabbit choledochal models reveal that the coating improves the durability and longevity of the stent. The implications of these findings suggest the potential COF-based Mg alloy stent surface treatments and a leap forward in advancing stent performance and endurance in clinical applications.
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