title: PLCγ1-PKCγ signaling-mediated Hsp90α plasma membrane translocation facilitates tumor metastasis.
abstract: 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 (PLCγ1) by its siRNA or inhibitor prevents the accumulation of Hsp90α at cell protrusions. Inhibition of the downstream effectors of PLCγ1, including Ca(2+) and protein kinase C (PKCγ), also blocks the membrane translocation of Hsp90α, while activation of PKCγ leads to increased levels of cell-surface Hsp90α. Moreover, overexpression of PKCγ increases extracellular vesicle release, on which Hsp90α is present. Furthermore, activation or overexpression of PKCγ promotes tumor cell motility in vitro and tumor metastasis in vivo, whereas a specific neutralizing monoclonal antibody against Hsp90α inhibits such effects, demonstrating that PKCγ-induced Hsp90α translocation is required for tumor metastasis. Taken together, our study provides a mechanistic basis for the role for the PLCγ1-PKCγ pathway in regulating Hsp90α plasma membrane translocation, which facilitates tumor cell motility and promotes tumor metastasis.
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing, 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, 100084, China; Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Xin-an
authors.initials: XA
authors.lastname: Lu
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D051966:Phospholipase C gamma / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D018841:HSP90 Heat-Shock Proteins; C087857:protein kinase C gamma; D011493:Protein Kinase C; D051966:Phospholipase C gamma; D002118:Calcium
keywords: Hsp90α; PKCγ; PLCγ1; plasma membrane translocation; tumor invasion