Mutant p53 Drives Cancer Metastasis via RCP-Mediated Hsp90α Secretion

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 wildtype p53 (WTp53) suppresses the secretion of heat shock protein 90-alpha (Hsp90 alpha), whereas mutp53 enhances Hsp90 alpha vesicular trafficking and exosome-mediated secretion. Long-term delivery of an antibody that blocks extracellular Hsp90 alpha (eHsp90 alpha) 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 Hsp90 alpha secretion. RCP knockdown decreases eHsp90 alpha levels and inhibits malignant progression. Notably, recombinant Hsp90 alpha 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 Hsp90 alpha secretion and a strategy to treat human cancers expressing mutp53 proteins.