Phospholipid prunes actin branches

Starving tumors eat metabolic enzyme Xia et al. describe a way to force cancer cells to destroy a key metabolic enzyme they need to survive. Autophagy helps cancer cells survive the stressful environment inside a tumor. However, blocking the process doesn’t kill cancer cells, so researchers have been looking for a way to make cells vulnerable to autophagy shutdown. Xia et al. used an ovarian cancer cell line that is resistant to the autophagy inhibitor spautin-1 or an upgraded version of this molecule. After screening more than 8,200 compounds, they found that quizartinib was the most effective at restoring the cells’ vulnerability to either of the autophagy blockers. Quizartinib inhibits FLT3, a receptor tyrosine kinase that spurs growth and differentiation of hematopoietic precursor cells. The team found that quizartinib and the improved version of spautin-1 killed tumor cells from a variety of cell lines while leaving noncancerous kidney cells unscathed. Treating cancer cells with quizartinib alone inhibited glycolysis and activated macroautophagy, the best known type of autophagy in which the cell digests a large portion of its contents. In contrast, cells that received both compounds couldn’t initiate macroautophagy, but they switched on chaperone-mediated autophagy, a selective form of the process that eliminates individual molecules. Xia et al. noticed that cells that had activated chaperonemediated autophagy were low on ATP, so they determined which proteins the process was destroying. One of its targets was the enzyme hexokinase II, which is crucial for glucose metabolism and is often overexpressed in cancer cells. By eliminating hexokinase II, quizartinib and the autophagy inhibitor may prevent cancer cells from metabolizing absorbed glucose and mobilizing stored nutrients. The study provides evidence that combining an FLT3 inhibitor with an autophagy blocker could be a new way to treat cancer. Xia, H.-g., et al. 2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201503044