Project description:MCF-7 breast cancer cells were treated with two novel anti-cancer compounds, SIMR_3058 and SIMR_3066, and the metabolome and proteome analysed by LC-MS/MS using a timsTOF.
Project description:Cancer is a major health concern worldwide, necessitating the discovery of more targeted approaches adequate management and therapy of tumors that are especially malignant, such as triple-negative breast cancer (TNBC). Through various biochemical studies carried out on TNBC, the MAPK pathway was implicated in cancer progression. MAPK involves the activation of multiple kinases, one of which is the C-RAF kinase. Therefore, small-molecule kinase inhibitors that can inhibit C-RAF and the MAPK pathway are of great interest in cancer research. This study investigates two C-RAF kinase inhibitors synthesized as quinoline-containing small molecules based on the design of the established kinase inhibitor sorafenib and other lead compounds. MDA-MB-468 and BT-549, both TNBC cell lines, were treated with the compounds separately and in combination, followed by metabolomics and proteomics analyses using LC-MS/MS. Upon identifying altered metabolic pathways and dysregulated proteins, the compounds’ mechanisms of action were found to involve DNA damage and repair, tRNA synthesis, protein expression, and energy production. The combination of the two C-RAF kinase inhibitors on TNBC cell lines led to earlier impact on amino acid metabolism and subsequent protein expression. This study hopes to enrich the current understanding of cancer biochemistry and reveal key biomarkers which can ultimately be targeted cancer therapies.
Project description:Inhalation of toxic chemicals, including recent e-cigarettes, often cause life-threatening lung injury. Although exposure to polyhexamethylene guanidine (PHMG)-containing humidifier disinfectant (HD) has been identified as a cause of fatal lung injury, the mechanism underlying HD-associated lung injury (HDLI) is unknown. The present study evaluated global changes in gene expression in lung tissues from patients with PHMG-induced HDLI, and compared gene expression changes in PHMG-induced rat lung tissues. Significantly different expressions in lung tissues between patients with HDLI and unaffected controls were observed. Furthermore, several fibrosis-associated overlapping genes (such as MMP2 and COL1A2) shared between humans with HDLI and rats exposed to PHMG were identified. Interactome network analysis predicted different pathways between children and adults with HDLI: the TGFβ/SMAD signaling pathway was central in adults, whereas other pathways, including integrin signaling, were associated with HDLI in children. Further interactome network analysis revealed that Rap1 and CCKR signaling pathways were significantly enriched in HDLI compared with idiopathic pulmonary fibrosis as well as their recapitulation in the lung tissues of rats exposed to PHMG. Our results suggest that MMP2-mediated different mechanisms between children and adults may be associated with PHMG-induced HDLI development, and Rap1 and CCKR pathways appear to be crucial.
Project description:Inhalation of toxic chemicals, including recent e-cigarettes, often cause life-threatening lung injury. Although exposure to polyhexamethylene guanidine (PHMG)-containing humidifier disinfectant (HD) has been identified as a cause of fatal lung injury, the mechanism underlying HD-associated lung injury (HDLI) is unknown. The present study evaluated global changes in gene expression in lung tissues from patients with PHMG-induced HDLI, and compared gene expression changes in PHMG-induced rat lung tissues. Significantly different expressions in lung tissues between patients with HDLI and unaffected controls were observed. Furthermore, several fibrosis-associated overlapping genes (such as MMP2 and COL1A2) shared between humans with HDLI and rats exposed to PHMG were identified. Interactome network analysis predicted different pathways between children and adults with HDLI: the TGFβ/SMAD signaling pathway was central in adults, whereas other pathways, including integrin signaling, were associated with HDLI in children. Further interactome network analysis revealed that Rap1 and CCKR signaling pathways were significantly enriched in HDLI compared with idiopathic pulmonary fibrosis as well as their recapitulation in the lung tissues of rats exposed to PHMG. Our results suggest that MMP2-mediated different mechanisms between children and adults may be associated with PHMG-induced HDLI development, and Rap1 and CCKR pathways appear to be crucial.