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Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640.
| Content Provider | Europe PMC |
|---|---|
| Author | Lewis, Clayton S. Voelkel-Johnson, Christina Smith, Charles D. |
| Copyright Year | 2016 |
| Abstract | Pancreatic cancer remains extremely difficult to treat, with the average lifespan following diagnosis being only 3-6 months, resulting in a death to incidence ratio of 0.94. A major reason for this high mortality rate is resistance to the main chemotherapeutic agent used to treat this disease, gemcitabine. Alterations in nucleoside and gemcitabine metabolism, specifically over-expression of ribonucleotide reductase, have been implicated as a major mechanism of resistance to this drug. Here, we show that inhibition of sphingosine kinase-2 by the specific inhibitor ABC294640 is synergistically cytotoxic with gemcitabine toward three human pancreatic cancer cell lines. Treatment with ABC294640 results in decreased expression of both RRM2 and MYC in all three cell lines. Additionally, expression of c-Myc protein and phosphorylation of Rb at S780 both decrease in a dose-dependent manner in response to ABC294640, while acetylation of H3-K9 and p21 levels increase. Pretreatment with the protein phosphatase 1 inhibitor okadaic acid or the ceramide synthase inhibitor fumonisin B1 fails to prevent the effects of ABC294640 on Rb phosphorylation. These data indicate a role for sphingosine kinase-2 in E2F and c-Myc mediated transcription through alteration of histone acetylation and p21 expression. These effects of ABC294640 suggest that it may be an effective agent for pancreatic cancer, particularly in combination with gemcitabine. |
| Journal | Oncotarget |
| Volume Number | 7 |
| PubMed Central reference number | PMC5312377 |
| Issue Number | 37 |
| PubMed reference number | 27517489 |
| e-ISSN | 19492553 |
| DOI | 10.18632/oncotarget.11112 |
| Language | English |
| Publisher | Impact Journals LLC |
| Publisher Date | 2016-09-01 |
| Access Restriction | Open |
| Rights License | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2016 Lewis et al. |
| Subject Keyword | sphingosine kinase-2 gemcitabine pancreatic cancer c-Myc ribonucleotide reductase |
| Content Type | Text |
| Resource Type | Article |
| Subject | Oncology |
