ASAH1-Triggered Autophagy Promotes the Tumorigenesis of Colorectal Cancer

Background: Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies, ranking third in morbidity and second in mortality among all cancers in the world. The dysregulation of acid ceramidase (ASAH1) which is involved in sphingolipid metabolism, is known to promote tumorigenesis. As an inhibitor of ASAH1, carmofur (1-hexylcarbamoyl-5-fluorouracil) is used as a chemotherapeutic agent clinically and plays a critical role in ASAH1-induced tumorigenesis. The aim of this study was to explore targeting ASAH1 as a new therapeutic mechanism for CRC.Methods: Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) assay were performed to detect protein expression levels and transcript expression levels. Lentivirus-mediated shRNA (short hairpin RNA) was used to silence ASAH1 and establish ASAH1-knockdown cell lines. Thiazolyl Blue Tetrazolium Bromide (MTT) assay, colony formation and transwell assay were performed to assess cell viability, colony formation ability, migration and invasion ability. Xenograft tumor model was established to study the therapeutic effect of ASAH1 inhibition on tumor growth.Results: Firstly, ASAH1 expression in CRC tissues was higher than normal tissues. In addition, ASAH1 inhibition decreased the proliferation of CRC cells and protected mice from the onset and progression of CRC in the xenograft tumor model. Moreover,ASAH1 was possibly associated with autophagy activation in DLD-1 cells. Conclusions: ASAH1 played a key role in regulating tumorigenesis and cell autophagy in CRC. Therefore, ASAH1 has the potential to be developed as a potential therapeutic target for preclinical studies in CRC.