Beloueche-Babari Mounia, Arunan Vaitha, Jackson L Elizabeth, Perusinghe Nina, Sharp Swee Y, Workman Paul, Leach Martin O
Cancer Research UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
Oncotarget. 2010 Jul;1(3):185-97. doi: 10.18632/oncotarget.125.
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.
分子伴侣热休克蛋白90（Hsp90）抑制剂是很有前景的靶向癌症治疗药物，其优点是能消耗多种致癌客户蛋白并调节癌症的所有经典特征。它们目前正处于临床试验阶段，在黑色素瘤和其他恶性肿瘤中显示出活性潜力。在此，我们使用磁共振波谱法探究了人类黑色素瘤细胞对Hsp90抑制的代谢反应。我们发现，在人类黑色素瘤细胞中，伴随着生长抑制和再分化，Hsp90抑制与甘油磷酸胆碱含量增加有关。基于临床格尔德霉素的Hsp90药物17-AAG以及结构不同的Hsp90抑制剂CCT018159均出现了这种情况。在BRAF突变的SKMEL28细胞和BRAF野生型CHL-1黑色素瘤细胞中均观察到了这种效应。在经17-AAG处理的SKMEL28细胞中还观察到-CH2+CH3脂肪酰链和细胞质可移动脂滴的含量升高。重要的是，磷脂酶A2抑制剂溴烯醇内酯可阻止17-AAG引起的甘油磷酸胆碱升高，这表明磷脂酶A2激活在Hsp90抑制剂诱导的代谢反应中起作用。我们的研究结果为将代谢变化用作Hsp90抑制的非侵入性指标以及可能用作恶性黑色素瘤及其他可能癌症中Hsp90药物抗癌活性的生物标志物提供了依据。
