Renal cell carcinoma (RCC) is among the top ten most common forms of
cancer and is the most common
malignancy of the kidney.
Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory
cancers with an incidence that is on the rise. Screening of
plant extracts in search of new anti-
cancer agents resulted in the discovery of
englerin A, a
guaiane sesquiterpene with potent cytotoxicity against
renal cancer cells and a small subset of other
cancer cells. Though a few cellular targets have been identified for
englerin A, it is still not clear what mechanisms account for the cytotoxicity of
englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of
englerin A. Metabolomics analyses indicated that
englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of
ceramides that were highly toxic to these cells. Microarray analyses determined that
englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that
englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of
englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other
lipid storing
cancers. Furthermore, our results suggest that
ceramides may be a mediator of some of the actions of
englerin A. Lastly, the acute inflammatory response induced by
englerin A may mediate anti-
tumor immunity.