STF-62247 blocks late stages of autophagy by disrupting lysosomal physiology

Abstract

ABSTRACTSTF-62247 was previously identified as a promising compound able to selectively target the loss of the tumor suppressor gene von Hippel-Lindau (VHL) in renal cell carcinomas. This present work investigates the effect of STF-62247 on the autophagic flux. Our investigations show that STF-62247 blocks late stages of autophagy through lysosomal disruption. Indeed, STF-62247 localizes at lysosomes and causes unregulated swelling of these acidic compartments in VHL-mutated cells, linking a potential role for VHL in lysosomal integrity. Knock-outs of BECN1 and ATG5 were able to rescue the viability of VHL-mutated cells in response to STF-62247 but did not rescue the lysosomal swelling. In fact, neutralizing the lysosomal pH by inhibiting the vacuolar H+-ATPase completely rescued this phenotype. Moreover, we show that STF-62247 disrupts endocytic routes and causes cathepsin D trafficking defects. This mechanistic study is the first to characterize STF-62447 as a novel lysosomotropic compound. Importantly, our study re-classifies STF-62247 as a blocker of later stages of autophagy and highlights its potential usage as a powerful new tool for endocytic and autophagy-related research.