The drebrin/EB3 pathway drives invasive activity in prostate cancer.
Prostate cancer is the most common cancer in men and the metastatic form of the disease is incurable. We show here that the drebrin/EB3 pathway, which co-ordinates dynamic microtubule/actin filament interactions underlying cell shape changes in response to guidance cues, plays a role in prostate cancer cell invasion. Drebrin expression is restricted to basal epithelial cells in benign human prostate but is upregulated in luminal epithelial cells in foci of prostatic malignancy. Drebrin is also upregulated in human prostate cancer cell lines and co-localizes with actin filaments and dynamic microtubules in filopodia of pseudopods of invading cells under a chemotactic gradient of the chemokine CXCL12. Disruption of the drebrin/EB3 pathway using BTP2, a small molecule inhibitor of drebrin binding to actin filaments, reduced the invasion of prostate cancer cell lines in 3D in vitro assays. Furthermore, gain- or loss-of-function of drebrin or EB3 by over-expression or siRNA-mediated knockdown increases or decreases invasion of prostate cancer cell lines in 3D in vitro assays, respectively. Finally, expression of a dominant-negative construct that competes with EB3 binding to drebrin, also inhibited invasion of prostate cancer cell lines in 3D in vitro assays. Our findings show that co-ordination of dynamic microtubules and actin filaments by the drebrin/EB3 pathway drives prostate cancer cell invasion and is therefore implicated in disease progression.
The MRC Centre for Developmental Neurobiology, King's College London, New Hunts House, Guy's Campus, London, UK.
A E
AE
Dart
The MRC Centre for Developmental Neurobiology, King's College London, New Hunts House, Guy's Campus, London, UK.
D C
DC
Worth
Urology, King's College Hospital, London, UK.
G
G
Muir
Cellular Pathology, 2nd floor North Wing, St. Thomas' Hospital, London, UK.
A
A
Chandra
Division of Cancer Studies, New Hunt's House, Guy's Campus, King's College London, London, UK.
J D
JD
Morris
Oxford Institute for Radiation Oncology, Churchill Hospital, University of Oxford, Oxford, UK.
C
C
McKee
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
C
C
Verrill
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
R J
RJ
Bryant
The MRC Centre for Developmental Neurobiology, King's College London, New Hunts House, Guy's Campus, London, UK.
P R
PR
Gordon-Weeks
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D045744:Cell Line, Tumor; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D013830:Thiadiazoles / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000199:Actins; D000813:Anilides; C403664:MAPRE3 protein, human; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D013830:Thiadiazoles; C053386:drebrins