SYK is a candidate kinase target for the treatment of advanced prostate cancer.
Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2β1 and CD44 were diminished. RNAi-mediated silencing of α2β1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2β1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer.
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Veerander P S
VP
Ghotra
Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden, the Netherlands.
Shuning
S
He
Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
Geertje
G
van der Horst
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Steffen
S
Nijhoff
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Hans
H
de Bont
Galapagos BV, Leiden, the Netherlands.
Annemarie
A
Lekkerkerker
Galapagos BV, Leiden, the Netherlands.
Richard
R
Janssen
Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Guido
G
Jenster
Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Geert J L H
GJ
van Leenders
Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
A Marije M
AM
Hoogland
Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Esther I
EI
Verhoef
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Zuzanna
Z
Baranski
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Jiangling
J
Xiong
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Bob
B
van de Water
Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
Gabri
G
van der Pluijm
Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden, the Netherlands. e.danen@lacdr.leidenuniv.nl b.e.snaar-jagalska@biology.leidenuniv.nl.
B Ewa
BE
Snaar-Jagalska
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands. e.danen@lacdr.leidenuniv.nl b.e.snaar-jagalska@biology.leidenuniv.nl.
Erik H J
EH
Danen
D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D000072377:Syk Kinase; D015027:Zebrafish
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse