FTY720, a fungus metabolite, inhibits invasion ability of androgen-independent prostate cancer cells through inactivation of RhoA-GTPase.
The failure of controlling androgen-independent and metastatic prostate cancer growth is the main cause of death in prostate cancer patients. In this study, we have demonstrated evidence on the inhibitory effects of a fungus metabolite, FTY720, on the clonogenesity as well as invasion ability of androgen-independent prostate cancer cells. First, using colony forming assay, we found that FTY720 treatment led to decreased colony forming ability of androgen-independent prostate cancer cell lines DU145 and PC3, indicating its negative role on cancer cell survival. In addition, treatment with relatively low dose of FTY720 (i.e. inhibitory concentration of 50% cell survival) resulted in suppression of prostate cancer cell migration and invasion abilities demonstrated by Wound closure, 3D collagen gel invasion assays and stress fiber staining. Furthermore, we found that the inhibitory effect of FTY720 on prostate cancer invasion was associated with down-regulation of GTP-bound active form of RhoA. Transfection of a dominant-active RhoA vector in DU145 and PC3 cells conferred resistance to FTY720. Since activation of RhoA-GTPase is associated with metastasis in many types of malignancies, our results not only suggest a new agent for the treatment of advanced prostate cancer, but also implicate a possible novel anticancer drug especially against metastatic cancers.
Cancer Biology Group, Department of Anatomy, Laboratory Block, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China.
Chun
C
Zhou
Ming-Tat
MT
Ling
Terence
T
Kin-Wah Lee
Kwan
K
Man
Xianghong
X
Wang
Yong-Chuan
YC
Wong
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011409:Propylene Glycols / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D011409:Propylene Glycols; D020742:rhoA GTP-Binding Protein; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine