ABSTRACT
BACKGROUND: Ketone ß-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof. METHODS: CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro. RESULTS: Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function. CONCLUSIONS: ß-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.
Subject(s)
3-Hydroxybutyric Acid , Cell Proliferation , Colorectal Neoplasms , Drug Resistance, Neoplasm , Histones , Oxaliplatin , Oxaliplatin/pharmacology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Humans , 3-Hydroxybutyric Acid/pharmacology , Animals , Mice , Histones/metabolism , Methylation , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Male , Epithelial-Mesenchymal Transition/drug effects , Female , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Movement/drug effects , Apoptosis/drug effects , Mice, NudeABSTRACT
A novel membrane detector is developed by a facile strategy combining commercialized membrane and smart nanogels for ultrasensitive and highly selective real-time detection of trace threat substances. On the basis of nanogel filtration and polydopamine adhesion, the membrane detector is fabricated by simply immobilizing smart nanogels onto the multiple pores of a commercialized membrane as the nanosensors and nanovalves. This is demonstrated by incorporating Pb2+-responsive poly( N-isopropylacrylamide- co-acryloylamidobenzo-18-crown-6) nanogels in the straight pores of a commercialized polycarbonate membrane for ultrasensitive and highly selective real-time detection of trace Pb2+. When selectively recognizing the Pb2+ in solution, the smart nanogels in the membrane pores swell, which lead to trans-membrane flux change. Quantitative detection of Pb2+ concentration can be achieved by simply measuring the flow rate of the trans-membrane flow. Due to the multiple nanochannels of nanogel-immobilized pores in the membrane for Pb2+ sensing and flux regulating, ultrasensitive and highly selective real-time detection of trace Pb2+ with concentration as low as 10-10 mol L-1 can be achieved. The nanogel-immobilized membrane detector offers a flexible platform to create versatile new membrane detectors by incorporating diverse smart nanogels for ultrasensitive and highly selective real-time detection of different trace threat substances.