Modulation of melanoma cell phospholipid metabolism in response to heat shock protein 90 inhibition
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Beloueche-Babari, M., Arunan, V., Jackson, L. E., Perusinghe, N., Sharp, S. Y., Workman, P., Leach, M. O.
(2010)
Modulation of melanoma cell phospholipid metabolism in response to heat shock protein 90 inhibition.
ONCOTARGET, 1 (3).
pp. 185-197.
ISSN 1949-2553
Full text not available from this repository.
Abstract
Molecular chaperone heat shock protein 90 (Hsp90) inhibitors are promising targeted cancer therapeutic drugs, with the advantage that they deplete multiple oncogenic client proteins and modulate all the classical hallmarks of cancer. They are now in clinical trial and show potential for activity in melanoma and other malignancies. Here we explore the metabolic response to Hsp90 inhibition in human melanoma cells using magnetic resonance spectroscopy. We show that, concomitant with growth inhibition and re-differentiation, Hsp90 inhibition in human melanoma cells is associated with increased glycerophosphocholine content. This was seen with both the clinical geldanamycin-based Hsp90 drug 17-AAG and the structurally dissimilar Hsp90 inhibitor CCT018159. The effect was noted in both BRAF mutant SKMEL28 and BRAF wildtype CHL-1 melanoma cells. Elevated content of the -CH2+CH3 fatty acyl chains and cytoplasmic mobile lipid droplets was also observed in 17-AAG-treated SKMEL28 cells. Importantly, the phospholipase A2 inhibitor bromoenol lactone prevented the rise in glycerophosphocholine seen with 17-AAG, suggesting a role for phospholipase A2 activation in the Hsp90 inhibitor-induced metabolic response. Our findings provide a basis for using metabolic changes as non-invasive indicators of Hsp90 inhibition and potentially as biomarkers of anticancer activity with Hsp90 drugs in malignant melanoma and possibly in other cancers.
| Item Type: | Article |
|---|---|
| Authors (ICR Faculty only): | Leach, Martin and Workman, Paul |
| All Authors: | Beloueche-Babari, M., Arunan, V., Jackson, L. E., Perusinghe, N., Sharp, S. Y., Workman, P., Leach, M. O. |
| Research teams: | ICR divisions > Cancer Therapeutics > Signal Transduction & Molecular Pharmacology ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) ICR divisions > Radiotherapy and Imaging > Magnetic Resonance |
| Depositing User: | Users 10 not found. |
| Date Deposited: | 08 Mar 2011 09:41 |
| Last Modified: | 08 Mar 2011 09:41 |
| URI: | http://publications.icr.ac.uk/id/eprint/10371 |
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