Extracellular Hsp90? and clusterin synergistically promote breast cancer epithelial-to-mesenchymal transition and metastasis via LRP1.

Extracellular heat shock protein 90 alpha (eHsp90?, also known as HSP90AA1) 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 eHsp90? and mediate its pro-metastasis function. However, the regulatory ...
mechanism of eHsp90? activity remains largely unknown. Here, we report that clusterin, a protein newly demonstrated to interact with eHsp90?, modulates eHsp90? signaling. We found that clusterin potentiated the effects of eHsp90? on activation of the AKT, ERK and NF-?B protein families, epithelial-to-mesenchymal transition (EMT) and migration in breast cancer cells. Furthermore, in vivo investigations demonstrated similar synergistic effects of eHsp90? and clusterin on tumor metastasis. Notably, the effects of eHsp90? 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 eHsp90?-LRP1 complex formation, which enhanced the binding affinity of eHsp90? to LRP1. Collectively, our data establish a role of clusterin as a newly discovered modulator of eHsp90?, and unravel detailed molecular mechanisms underlying the synergistic metastasis-promoting effects of clusterin and eHsp90?.
Mesh Terms:
Breast Neoplasms, Clusterin, Epithelial-Mesenchymal Transition, Female, HEK293 Cells, HSP90 Heat-Shock Proteins, Humans, Low Density Lipoprotein Receptor-Related Protein-1, MAP Kinase Signaling System, MCF-7 Cells, Neoplasm Metastasis, Neoplasm Proteins
J Cell Sci
Date: Dec. 31, 2018
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