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Differential Expression of the Sphingolipid Pathway Is Associated with Sensitivity to the PP2A Activator FTY720 in
Peter Sciberras1, Laura Grech1, Godfrey Grech1
1Department of Pathology, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta.
Abstract:
Protein phosphatase 2A (PP2A) is a ubiquitously expressed intracellular serine/threonine phosphatase. Deregulation of PP2A is a common event associated with adenocarcinomas of the colon and rectum. We have previously shown that breast cancer cell lines are sensitive to the PP2A activator FTY720, and that sensitivity is predicted by high Aurora kinase A (AURKA) mRNA expression. In this study, we hypothesized that high relative AURKA expression could predict sensitivity to FTY720-induced apoptosis in colorectal cancer (CRC). The CRC cell lines NCI H716, COLO320DM, DLD-1, SW480, and HT-29 show a high relative AURKA expression as compared to LS411N, T84, HCT116, SW48, and LOVO. Following viability assays, LS411N, T84, HCT116, and SW480 were shown to be sensitive to FTY720, whereas DLD-1 and HT-29 were non-sensitive. Hence, AURKA mRNA expression does not predict sensitivity to FTY720 in CRC cell lines. Differentially expressed genes (DEGs) were obtained by comparing the sensitive CRC cell lines (LS411N and HCT116) against the non-sensitive (HT-29 and DLD-1). We found that 253 genes were significantly altered in expression, and upregulation of CERS4, PPP2R2C, GNAZ, PRKCG, BCL2, MAPK12, and MAPK11 suggests the involvement of the sphingolipid signaling pathway, known to be activated by phosphorylated-FTY720. In conclusion, although AURKA expression did not predict sensitivity to FTY720, it is evident that specific CRC cell lines are sensitive to 5 µM FTY720, potentially because of the differential expression of genes involved in the sphingolipid pathway.
Insights
High Aurora kinase A (AURKA) expression does not predict sensitivity to FTY720 in colorectal cancer (CRC) cell lines. However, specific CRC cell lines show sensitivity to FTY720, linked to the sphingolipid signaling pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Protein phosphatase 2A (PP2A) deregulation is common in colorectal cancer (CRC).
- FTY720, a PP2A activator, shows promise in cancer therapy.
- Previous studies linked FTY720 sensitivity in breast cancer to Aurora kinase A (AURKA) mRNA expression.
Purpose of the Study:
- To investigate if high AURKA mRNA expression predicts FTY720 sensitivity in CRC cell lines.
- To identify molecular mechanisms underlying FTY720 sensitivity in CRC.
Main Methods:
- Assessed FTY720 sensitivity in CRC cell lines using viability assays.
- Compared AURKA mRNA expression levels across different CRC cell lines.
- Analyzed differentially expressed genes (DEGs) between FTY720-sensitive and non-sensitive CRC cell lines.
Main Results:
- AURKA mRNA expression did not correlate with FTY720 sensitivity in CRC cell lines.
- Specific CRC cell lines (LS411N, T84, HCT116, SW480) were sensitive to 5 µM FTY720.
- Upregulation of genes in the sphingolipid signaling pathway (e.g., CERS4, PPP2R2C, GNAZ, PRKCG, BCL2, MAPK12, MAPK11) was observed in sensitive cell lines.
Conclusions:
- AURKA expression is not a reliable predictor of FTY720 sensitivity in CRC.
- FTY720 demonstrates efficacy in a subset of CRC cell lines.
- The sphingolipid signaling pathway may mediate FTY720's effects in CRC.
