eHsp90α and clusterin synergistically promote breast cancer epithelial-to-mesenchymal transition and metastasis via LRP1

Abstract

Extracellular heat shock protein 90 alpha (eHsp90α) has been widely reported to promote tumor cell motility and tumor metastasis in various types of cancer. Several extracellular proteins and membrane receptors have been identified as interacting proteins of eHsp90α and mediate its pro-metastasis function. However, the regulatory mechanism of eHsp90α activity remains largely unknown. Here, we reported that clusterin, a novel interacting protein of eHsp90α, modulated eHsp90α signaling. We found that clusterin potentiated the effects of eHsp90α on the activation of AKT, ERK, NF-κB, epithelial-to-mesenchymal transition (EMT) and migration in breast cancer cells. Furthermore, in vivo investigations demonstrated similar synergistic effects of eHsp90α and clusterin on tumor metastasis. Notably, the effects of eHsp90α and clusterin were mediated by low-density lipoprotein receptor-related protein 1 (LRP1). Proximity ligation assay and co-immunoprecipitation experiments demonstrated that clusterin participated in the complex formation of eHsp90α and LRP1, which enhanced the binding affinity of eHsp90α to LRP1. Collectively, our data establish a role of clusterin as a novel modulator of eHsp90α, and unravel detailed molecular mechanisms underlying the synergistic metastasis-promoting effects of clusterin and eHsp90α.