Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation.
BACKGROUND
We previously reported that FTY720, a metabolite from Isaria sinclairii, induced some cancer cells to undergo apoptosis, and that FTY720-induced apoptosis was not related to Fas-antigens. In this study we investigated whether FTY720 was able to induce apoptosis in an androgen-independent prostate cancer cell line, DU145, which is not only resistant to androgen-withdrawal-induced apoptosis but also Fas- and TNF-alpha-mediated apoptosis.


METHODS
Cell survival and morphological change were examined and apoptosis was confirmed by DNA isolation and analysis of DNA fragmentation. Caspase activation was studied by using anti-caspase-1 and anti-caspase-3 antibodies. To determine whether caspase activation is central to FTY720-induced apoptosis, caspase inhibitor was added to the media 24 hr prior to the addition of FTY720.


RESULTS
We found that FTY720 rapidly induced apoptosis in DU145 cells, and that caspase-3 was activated during FTY720-induced apoptosis. In contrast, normal human prostate stromal cells were resistant to FTY720. Furthermore, FTY720-induced apoptosis was prevented by caspase-3 inhibitor.


CONCLUSIONS
The data in this report show that FTY720 is a potential strong antitumor agent for cell line DU145, and provide the first evidence for involvement of caspase-3 in apoptosis of an androgen-independent prostate cancer cell line. Activation of such caspases may provide a means for eliminating androgen-independent prostate cancer in humans.
Wang
J D
JD
Department of Urology, Osaka University Medical School, Suita-city, Japan.
Takahara
S
S
Nonomura
N
N
Ichimaru
N
N
Toki
K
K
Azuma
H
H
Matsumiya
K
K
Okuyama
A
A
Suzuki
S
S
D000728:Androgens / Q000502:physiology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008297:Male; D011409:Propylene Glycols / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000728:Androgens; D011409:Propylene Glycols; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine