Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance

  • Authors:
    • James W. Antoon
    • Martin D. White
    • Matthew E. Burow
    • Barbara S. Beckman
  • View Affiliations

  • Published online on: March 27, 2012     https://doi.org/10.3892/or.2012.1743
  • Pages: 1779-1786
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Abstract

Recent research has demonstrated that aberrant sphingolipid signaling is an important mechanism of chemoresistance in solid tumors. Sphingosine kinase (Sphk), the primary enzyme metabolizing the sphingolipid ceramide into sphingosine-1-phosphate (S1P), is a primary mediator of breast cancer promotion, survival and chemoresistance. However, to date the mechanism of Sphk-mediated drug resistance is poorly understood. Using the dual sphingosine kinase isozyme inhibitor, SKI-II (4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol), we explored the effects of sphingosine kinase inhibition on multi-drug-resistant breast cancer cells. We demonstrate that SKI-II alters endogenous sphingolipid signaling and decreases cancer proliferation, survival and viability. Furthermore, pharmacological inhibition of Sphk1/2 induced intrinsic apoptosis in these cells through modulation of the NF-κB pathway. SKI-II decreases NF-κB transcriptional activity through altered phosphorylation of the p65 subunit. Taken together, these results suggest that Sphk may be a promising therapeutic target in chemoresistant cancers.

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June 2012
Volume 27 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Antoon JW, White MD, Burow ME and Beckman BS: Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance. Oncol Rep 27: 1779-1786, 2012
APA
Antoon, J.W., White, M.D., Burow, M.E., & Beckman, B.S. (2012). Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance. Oncology Reports, 27, 1779-1786. https://doi.org/10.3892/or.2012.1743
MLA
Antoon, J. W., White, M. D., Burow, M. E., Beckman, B. S."Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance". Oncology Reports 27.6 (2012): 1779-1786.
Chicago
Antoon, J. W., White, M. D., Burow, M. E., Beckman, B. S."Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance". Oncology Reports 27, no. 6 (2012): 1779-1786. https://doi.org/10.3892/or.2012.1743