SU6668 modulates prostate cancer progression by downregulating MTDH/AKT signaling pathway.
Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although diagnosis modalities for primary prostate cancer have markedly improved, there are still no effective therapies for metastatic prostate cancer. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2, PDGFRβ and FGFR1. There is strong experimental evidence that SU6668 can induce growth inhibition of various primary tumors. However, the function and molecular mechanism of SU6668 in prostate cancer has not been fully elucidated. In the present study, we found that SU6668 inhibited the proliferation and invasion of prostate cancer cells. Functional studies also demonstrated that SU6668 inhibited epithelial-mesenchymal transition in DU145 and LNCap cells. After treatment with SU6668, MTDH protein, which has been reported to be significantly overexpressed in many human tumor tissues, was downregulated in DU145 and LNCap cells. siRNA-mediated silencing of MTDH in prostate cancer cells decreased their proliferation and invasive capabilities, suggesting that SU6668 may inhibit cell proliferation and invasion of prostate cancer cells partly through downstream targeting of MTDH. Mechanistic investigations showed that AKT signaling pathway was inhibited after SU6668 treatment in prostate cancer cells. Moreover, a combination of SU6668 and PI3K-AKT pathway inhibitor LY29004 resulted in increased inhibition of cell proliferation and invasion in DU145 cells. Taken together, our findings revealed that SU6668 suppressed prostate cancer progression by downregulating MTDH/AKT signaling pathway and identified a promising therapeutic strategy for prostate cancer.
Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, Fu'an, Fujian 355000, P.R. China.
Benjiang
B
Qian
Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, Fu'an, Fujian 355000, P.R. China.
Yi
Y
Yao
Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, Fu'an, Fujian 355000, P.R. China.
Changming
C
Liu
Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, Fu'an, Fujian 355000, P.R. China.
Jiabing
J
Zhang
Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, Fu'an, Fujian 355000, P.R. China.
Huihong
H
Chen
Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, Fu'an, Fujian 355000, P.R. China.
Huizhang
H
Li
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D000078183:Oxindoles; D011422:Propionates; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage; D016601:RNA-Binding Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D015815:Cell Adhesion Molecules; D007211:Indoles; C483039:MTDH protein, human; D008565:Membrane Proteins; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D016601:RNA-Binding Proteins; C412603:orantinib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt