PLCγ1–PKCγ Signaling‐Mediated Hsp90α Plasma Membrane Translocation Facilitates Tumor Metastasis

The 90‐kDa heat shock protein (Hsp90α) 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 Hsp90α plasma membrane translocation during tumor invasion remains poorly understood. Here, we show that Hsp90α 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 γ1) by its siRNA or inhibitor prevents the accumulation of Hsp90α at cell protrusions. Inhibition of the downstream effectors of PLC γ1, including Ca 2+ and protein kinase C ( PKC γ), also blocks the membrane translocation of Hsp90α , while activation of PKC γ leads to increased levels of cell‐surface Hsp90α . Moreover, overexpression of PKC γ increases extracellular vesicle release, on which Hsp90α is present. Furthermore, activation or overexpression of PKC γ promotes tumor cell motility in vitro and tumor metastasis in vivo , whereas a specific neutralizing monoclonal antibody against Hsp90α inhibits such effects, demonstrating that PKC γ‐induced Hsp90α translocation is required for tumor metastasis. Taken together, our study provides a mechanistic basis for the role for the PLC γ1– PKC γ pathway in regulating Hsp90α plasma membrane translocation, which facilitates tumor cell motility and promotes tumor metastasis.