PLCγ1-PKCγ Signaling-Mediated Hsp90α Plasma Membrane Translocation Facilitates Tumor Metastasis

The 90-kDa heat shock protein (Hsp90 alpha) has been identified on the surface of cancer cells, and is implicated in tumor invasion and metastasis, suggesting that it is a potentially important target for tumor therapy. However, the regulatory mechanism of Hsp90a plasma membrane translocation during tumor invasion remains poorly understood. Here, we show that Hsp90a plasma membrane expression is selectively upregulated upon epidermal growth factor (EGF) stimulation, which is a process independent of the extracellular matrix. Abrogation of EGF-mediated activation of phospholipase (PLC gamma 1) by its siRNA or inhibitor prevents the accumulation of Hsp90a at cell protrusions. Inhibition of the downstream effectors of PLC gamma 1, including Ca2+ and protein kinase C (PKC gamma), also blocks the membrane translocation of Hsp90a, while activation of PKC. leads to increased levels of cell-surface Hsp90a. Moreover, overexpression of PKC. increases extracellular vesicle release, on which Hsp90a is present. Furthermore, activation or overexpression of PKC. promotes tumor cell motility in vitro and tumor metastasis in vivo, whereas a specific neutralizing monoclonal antibody against Hsp90a inhibits such effects, demonstrating that PKC gamma-induced Hsp90a translocation is required for tumor metastasis. Taken together, our study provides a mechanistic basis for the role for the PLC gamma 1-PKC. pathway in regulating Hsp90a plasma membrane translocation, which facilitates tumor cell motility and promotes tumor metastasis.