ABSTRACT
Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assay, glucose uptake assay, Oil Red O staining, cell viability assay, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mammalian target of rapamycin (mTOR) signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, and glucose uptake, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.NEW & NOTEWORTHY Transcription factor forkhead box M1 (FOXM1) regulates glycolysis, fatty acid biosynthesis, and cellular energy consumption, which, together, controls cell growth and patient prognosis in colorectal cancer (CRC).
Subject(s)
Colorectal Neoplasms , Forkhead Box Protein M1 , Humans , Forkhead Box Protein M1/metabolism , Forkhead Box Protein M1/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , HT29 Cells , HCT116 Cells , Glycolysis , Gene Expression Regulation, Neoplastic , Warburg Effect, Oncologic , Signal Transduction , Cell Proliferation , Cellular Reprogramming/physiology , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Metabolic ReprogrammingABSTRACT
A palladium(II)-catalyzed C-H arylation directed by tetrazole, a metabolically stable surrogate for the carboxylic acid group in drug design, has been developed. Excellent mono-/di-selectivity was achieved through adjustment of the protecting site on the tetrazole ring. The synthetic utility of this new transformation was demonstrated in the concise total synthesis of Losartan.