Abstract

Summary Mutant p53 (mutp53) loses its tumor suppressor properties but gains oncogenic functions of driving malignancy. However, it remains largely unknown how mutp53 drives cancer metastasis. Here, we show that wild-type p53 (WTp53) suppresses the secretion of heat shock protein 90-alpha (Hsp90α), whereas mutp53 enhances Hsp90α vesicular trafficking and exosome-mediated secretion. Long-term delivery of an antibody that blocks extracellular Hsp90α (eHsp90α) function extends the survival of p53 −/− mice and attenuates the invasiveness of p53 mutant tumors. Furthermore, mass spectrometry and functional analysis identified a critical role for Rab coupling protein (RCP) in mutp53-induced Hsp90α secretion. RCP knockdown decreases eHsp90α levels and inhibits malignant progression. Notably, recombinant Hsp90α re-introduction markedly rescues the impaired migration and invasion abilities caused by RCP depletion. Taken together, these findings elucidate the molecular mechanisms by which mutp53 executes oncogenic activities via its downstream RCP-mediated Hsp90α secretion and a strategy to treat human cancers expressing mutp53 proteins.