SK1 Inhibitor RB005 Induces Apoptosis in Colorectal Cancer Cells through SK1 Inhibition Dependent and Independent Pathway
| Autor: | Maftuna Shamshiddinova, Jitendra Shrestha, Yong-Moon Lee, Dong Jae Baek, Yoon Sin Oh, Eun Young Park |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Ceramide
Programmed cell death Fingolimod Hydrochloride Colorectal cancer Activator (genetics) Angiogenesis Cell growth Sphingosine kinase Apoptosis General Medicine Ceramides medicine.disease chemistry.chemical_compound chemistry Colonic Neoplasms medicine Cancer research Humans RNA Small Interfering Colorectal Neoplasms |
| Zdroj: | Current Molecular Pharmacology. 15:570-581 |
| ISSN: | 1874-4672 |
| DOI: | 10.2174/1874467214666210811151324 |
| Popis: | Background and Objective: Colorectal cancer (CRC) is the fourth leading cause of cancer- related death globally, with a high incidence rate in economically fast-growing countries. Sphingosine- 1-phosphate (S1P) is a bioactive lipid mediator that plays critical roles in cancer cell proliferation, migration, and angiogenesis converted by the isoforms of sphingosine kinase (SK1 and SK2). SK1 is highly expressed in colorectal cancer; its inhibitors suppress the formation of S1P and increase ceramide levels having a pro-apoptotic function. RB005 is a selective SK1 inhibitor and a structural analog of PP2A activator FTY720. The purpose of this study is to test whether RB005, an SK1 inhibitor, can be used as an anticancer agent by inhibiting the growth of colon cancer cells. Methods: We performed MTT and colony-forming assay using colon cancer cell lines HT29 and HCT116 cells to examine the cell toxicity effect of RB005. To determine whether apoptosis of RB005 in colon cancer cell line is due to SK1 inhibition or other mechanisms due to its structural similarity with FTY720, we conducted LC/MS, siRNA knockdown, and PP2A activity experiments. Results: RB005 notably inhibited CRC cell growth and proliferation compared to PF543 and ABC294640 by inducing the mitochondria-mediated intrinsic apoptotic pathway. Apoptotic cell death is caused by increased mitochondrial permeability Initiated by the activation of pro-apoptotic protein BAX, increased ceramides, and activation of PP2A. Also, RB005 treatment in HT29 cells did not change the expression level of SK1, but strikingly decreased SK1 activity and S1P levels. All these events of cell death and apoptosis were less effective when SK1 was knocked down by siRNA. Conclusion: This result indicates that RB005 shows the in-vitro anti-CRC effect by inhibiting SK1 activity and PP2A activation, increasing proapoptotic ceramide levels following the activation of the intrinsic apoptotic pathway. |
| Databáze: | OpenAIRE |
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