TY - JOUR
T1 - Serum caveolin-1, a biomarker of drug response and therapeutic target in prostate cancer models
AU - Tahir, Salahaldin A.
AU - Kurosaka, Shinji
AU - Tanimoto, Ryuta
AU - Goltsov, Alexei A.
AU - Park, Sanghee
AU - Thompson, Timothy C.
N1 - Funding Information:
The authors thank Karen F. Phillips, ELS, for her expert editorial assistance and Dr Jianxiang Wang for technical assistance. This work was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (CA016672) and grant R01CA68814 (to T.C.T.) and by the United States Department of Defense grant DAMD 17-98-11-8575 (to T.C.T.).
PY - 2013/2
Y1 - 2013/2
N2 - We investigated the effect of dasatinib and sunitinib on tyrosine kinase (TK) signaling, caveolin-1 (Cav-1) expression and secretion and proliferation of PC-3 and DU145 prostate cancer cells in vitro and in vivo. Treatment of both cell lines with either dasatinib or sunitinib reduced phosphorylation of PDGFR, VEGFR2, Akt, FAK, Src (dasatinib only) and Cav-1, and reduced cellular and secreted levels of Cav-1. Both agents dose-dependently inhibited proliferation of these cells. In PC-3 and DU145 subcutaneous xenografts, treatment with dasatinib, sunitinib or anti-Cav-1 antibody (Ab) alone produced significant tumor regression compared with that by vehicle or IgG alone. Combined dasatinib and anti-Cav-1 Ab treatment or sunitinib and anti-Cav-1 Ab produced greater tumor regression than either treatment alone. Serum Cav-1 levels were lower in dasatinib- and sunitinib-treated mice than they were in vehicle-treated mice, and correlated positively with tumor growth in dasatinib- and sunitinib-treated groups (r = 0.48, p = 0.031; r = 0.554, p = 0.0065, respectively), compared with vehicle controls. Cav-1 knockdown, in combination with dasatinib or sunitinib treatment in PC-3 cells, caused a greater reduction in the phosphorylation of PDGFR-β and VEGFR2, and expression and secretion of PDGF-B and VEGF-A than that in PC-3 cells treated with dasatinib or sunitinib alone in control siRNA cells, suggesting that Cav-1 is involved in an autocrine pathway that is affected by these drugs. Overall, our results suggest a role for Cav-1 as a biomarker of response to both dasatinib and sunitinib treatment and as a therapeutic target in prostate cancer.
AB - We investigated the effect of dasatinib and sunitinib on tyrosine kinase (TK) signaling, caveolin-1 (Cav-1) expression and secretion and proliferation of PC-3 and DU145 prostate cancer cells in vitro and in vivo. Treatment of both cell lines with either dasatinib or sunitinib reduced phosphorylation of PDGFR, VEGFR2, Akt, FAK, Src (dasatinib only) and Cav-1, and reduced cellular and secreted levels of Cav-1. Both agents dose-dependently inhibited proliferation of these cells. In PC-3 and DU145 subcutaneous xenografts, treatment with dasatinib, sunitinib or anti-Cav-1 antibody (Ab) alone produced significant tumor regression compared with that by vehicle or IgG alone. Combined dasatinib and anti-Cav-1 Ab treatment or sunitinib and anti-Cav-1 Ab produced greater tumor regression than either treatment alone. Serum Cav-1 levels were lower in dasatinib- and sunitinib-treated mice than they were in vehicle-treated mice, and correlated positively with tumor growth in dasatinib- and sunitinib-treated groups (r = 0.48, p = 0.031; r = 0.554, p = 0.0065, respectively), compared with vehicle controls. Cav-1 knockdown, in combination with dasatinib or sunitinib treatment in PC-3 cells, caused a greater reduction in the phosphorylation of PDGFR-β and VEGFR2, and expression and secretion of PDGF-B and VEGF-A than that in PC-3 cells treated with dasatinib or sunitinib alone in control siRNA cells, suggesting that Cav-1 is involved in an autocrine pathway that is affected by these drugs. Overall, our results suggest a role for Cav-1 as a biomarker of response to both dasatinib and sunitinib treatment and as a therapeutic target in prostate cancer.
KW - Biomarkers
KW - Caveolin-1
KW - Prostate cancer
KW - Tyrosine kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84873472216&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873472216&partnerID=8YFLogxK
U2 - 10.4161/cbt.22633
DO - 10.4161/cbt.22633
M3 - Article
C2 - 23114714
AN - SCOPUS:84873472216
SN - 1538-4047
VL - 14
SP - 117
EP - 126
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 2
ER -
