Abstract
Sphingosine-1-phosphate lyase 1 (S1P lyase or SGPL1) is an essential sphingosine-1-phosphate-degrading enzyme. Its manipulation favors onset and progression of colorectal cancer and others in vivo. Thus, SGPL1 is an important modulator of cancer initiation. However, in established cancer, the impact of retrospective SGPL1 modulation is elusive. Herein, we analyzed how SGPL1 siRNA affects malignancy of the human colorectal cancer cells DLD-1 and found that in parallel to the reduction of SGPL1 expression levels, migration, invasion, and differentiation status changed. Diminished SGPL1 expression was accompanied with reduced cell migration and cell invasion in scratch assays and transwell assays, whereas metabolic activity and proliferation was not altered. Decreased migration was attended by increased cell-cell-adhesion through upregulation of E-cadherin and formation of cadherin-actin complexes. Spreading cell islets showed lower vimentin abundance in border cells. Furthermore, SGPL1 siRNA treatment induced expression of epithelial cell differentiation markers, such as intestinal alkaline phosphatase and cytokeratin 20. Hence, interference with SGPL1 expression augmented a partial redifferentiation of colorectal cancer cells toward normal colon epithelial cells. Our investigation showed that SGPL1 siRNA influenced tumorigenic activity of established colorectal cancer cells. We therefore suggest SGPL1 as a target for lowering malignant potential of already existing cancer.
Highlights
Endogenous sphingolipids and their metabolizing enzymes are known to play an important role in progression, growth, and resistance to therapeutic treatment of human colorectal cancer (Camp et al, 2017)
We aimed to identify the role of SGPL1 in the human colorectal cancer cell line DLD-1 in the context of migration, proliferation, and differentiation to elucidate its role in the tumorigenic cellular activity of those cells
As vimentin is a marker of mesenchymal cells rather than epithelial cells and cell islet staining was reduced upon SGPL1 siRNA treatment, we suggested that the differentiation status of DLD-1 cells was altered per se
Summary
Endogenous sphingolipids and their metabolizing enzymes are known to play an important role in progression, growth, and resistance to therapeutic treatment of human colorectal cancer (Camp et al, 2017). A decrease in SGPL1 expression has been shown to reduce cell proliferation (Uranbileg et al, 2018), studies have demonstrated that loss of SGPL1 results in resistance to apoptotic effects induced by chemotherapeutic drugs and promotes oncogenesis (Colie et al, 2009). These data suggest that SGPL1 expression is strongly associated with the carcinogenic activation of colon epithelial cells and may distinctively affect cancer initiation versus progression in opposite directions
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