PLCγ1–PKCγ Signaling‐Mediated Hsp90α Plasma Membrane Translocation Facilitates Tumor Metastasis
Open Access
- 4 June 2014
- Vol. 15 (8), 861-878
- https://doi.org/10.1111/tra.12179
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 Ca2+ 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.Keywords
Funding Information
- National Natural Science Foundation of China (No. 81171998)
- National Natural Science Foundation of China (No. 81171999)
- National Natural Science Foundation of China (No. 81071742)
- Major Scientific and Technological Special Project for Significant New Drugs Creation (No. 2011ZX09101-001-08)
- Major Scientific and Technological Special Project for Significant New Drugs Creation (No. 2009ZX09102-243)
- National Science & Technology Major Project (No. 2009ZX09103-703)
- National Science & Technology Major Project (No. 2009ZX09306-002)
- Ph.D. Programs Foundation for New Teachers of Ministry of Education of China (No. 20110002120039)
This publication has 60 references indexed in Scilit:
- Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through METNature Medicine, 2012
- Secreted heat shock protein-90 (Hsp90) in wound healing and cancerBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2012
- The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and functionNature Reviews Molecular Cell Biology, 2011
- Pigment Epithelium-derived Factor and Its Phosphomimetic Mutant Induce JNK-dependent Apoptosis and p38-mediated Migration ArrestJournal of Biological Chemistry, 2011
- The Regulatory Mechanism of Extracellular Hsp90α on Matrix Metalloproteinase-2 Processing and Tumor AngiogenesisPublished by Elsevier BV ,2010
- Matrix Metalloproteinases: Regulators of the Tumor MicroenvironmentCell, 2010
- The regulatory mechanism of Hsp90α secretion and its function in tumor malignancyProceedings of the National Academy of Sciences of the United States of America, 2009
- Rab GTPases as coordinators of vesicle trafficNature Reviews Molecular Cell Biology, 2009
- A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasionOncogene, 2007
- Extracellular heat shock protein-90α: linking hypoxia to skin cell motility and wound healingThe EMBO Journal, 2007