Background It has been manifested in several studies that age-related metabolic reprogramming is associated with tumor progression, in particular, colorectal cancer (CRC). Here we investigated the role of upregulated metabolites of the aged serum, including methylmalonic acid (MMA), phosphoenolpyruvate (PEP), and quinolinate (QA), in CRC. Methods Functional assays including CCK-8, EdU, colony formation and transwell experiments were used to ascertain which upregulated metabolite of elderly serum was related to tumor progression. RNA-seq analysis was conducted to explore the potential mechanisms of MMA-induced CRC progression. Subcutaneous tumorigenesis and metastatic tumor models were constructed to verify the function of MMA in vivo. Results Among three consistently increased metabolites of the aged sera, MMA was responsible for tumorigenesis and metastasis in CRC, according to functional assays. The promotion of Epithelial–mesenchymal transition (EMT) was observed in CRC cells treated with MMA, on the basis of protein expression of EMT markers. Moreover, combined with transcriptome sequencing, Wnt/β-catenin signaling pathway was activated in CRC cells treated with MMA, which was verified by western blot and qPCR experiments. Furthermore, animal assays demonstrated the pro-proliferation and promotion of metastasis role of MMA in vivo. Conclusion We have identified that age-dependent upregulation of MMA in serum promoted the progression of CRC via Wnt/β-catenin signaling pathway mediated EMT. These collective findings provide valuable insights into the vital role of age-related metabolic reprogramming in CRC progression and propose a potential therapeutic target for elderly CRC.
Lipid metabolism plays an important role in the occurrence and development of cancer, in particular, digestive system tumors such as colon cancer. Here, we investigated the role of the fatty acid-binding protein 5 ( FABP5 ) in colorectal cancer (CRC). We observed marked down-regulation of FABP5 in CRC. Data from functional assays revealed inhibitory effects of FABP5 on cell proliferation, colony formation, migration, invasion as well as tumor growth in vivo . In terms of mechanistic insights, FABP5 interacted with fatty acid synthase ( FASN ) and activated the ubiquitin proteasome pathway, leading to a decrease in FASN expression and lipid accumulation, moreover, suppressing mTOR signaling and facilitating cell autophagy. Orlistat, a FASN inhibitor, exerted anti-cancer effects both in vivo and in vitro . Furthermore, the upstream RNA demethylase ALKBH5 positively regulated FABP5 expression via an m 6 A-independent mechanism. Overall, our collective findings offer valuable insights into the critical role of the ALKBH5 / FABP5 / FASN/mTOR axis in tumor progression and uncover a potential mechanism linking lipid metabolism to development of CRC, providing novel therapeutic targets for future interventions.
BackgroundLipid metabolism plays an important role in the occurrence and development of cancer, in particular, digestive system tumors such as colon cancer. Here, we investigated the role of the fatty acid-binding protein 5 (FABP5) in colorectal cancer(CRC). MethodsTo this end, tissue microarray was initially used for analysis of FABP5 expression, followed by generation of stable cell lines with knockdown or overexpression of FABP5 for a series of functional assays including CCK-8, colony formation, EdU and transwell experiments. Co-IP, RNA-seq and omics-based lipid metabolism studies were further performed to explore the mechanisms of action of FABP5 in CRC. The function of FABP5 in vivo was analyzed with the aid of tumor xenograft and immunohistochemistry experiments. ResultsWe observed marked downregulation of FABP5 in CRC. Data from functional assays revealed inhibitory effects of FABP5 on cell proliferation, colony formation, migration, invasion as well as tumor growth in vivo. In terms of mechanistic insights, FABP5 interacted with fatty acid synthase (FASN) and activated the ubiquitin proteasome pathway, leading to a decrease in FASN expression and lipid accumulation, in turn, suppressing mTOR signaling and facilitating cell autophagy. Orlistat, a FASN inhibitor, exerted anticancer effects both in vivo and in vitro. Moreover, the upstream RNA demethylase ALKBH5 positively regulated FABP5 expression via an m 6 A-independent mechanism. ConclusionOur collective ndings offer valuable insights into the critical role of the FABP5/FASN axis in tumor progression and uncover a potential mechanism linking lipid metabolism to development of CRC, providing novel therapeutic targets for future interventions.
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