Prostate-specific antigen (PSA)-mediated proliferation, androgenic regulation and inhibitory effects of LY312340 in HOS-TE85 (TE85) human osteosarcoma cells.
BACKGROUND
PSA mediates growth factor responses that stimulate proliferation of prostatic and other cellular types. Androgen-sensitive TE85 human osteosarcoma cells were used to study PSA as a potential mediator of prostatic cancer growth and osseous metastasis.


METHODS
TE85 cells were probed for PSA mRNA and protein levels under testosterone (T)-replete and--depleted conditions. TE85 proliferative responses to PSA were evaluated in the absence and presence of LY312340, a monocyclic beta-lactam inhibitor of PSA enzymatic activity.


RESULTS
A 3.1-fold increase in PSA mRNA was observed following T stimulation. Low levels of immunoreactive PSA (iPSA) were detected in media of androgen-stimulated TE85 cells while iPSA was not found in control media. Conversely, iPSA was detected in TE85 cell pellets from control but not in androgen-stimulated cell cultures. Exogenously added enzymatically active PSA stimulated TE85 proliferation in a bi-phasic manner. LY312340 inhibited PSA-induced increases in TE85 cell numbers but had no effect on basal or T- stimulated cellular proliferation.


CONCLUSIONS
While the PSA levels produced by TE-85 cells in response to androgen stimulation are too low to be biologically active, PSA produced by metastatic PCa cells may mediate paracrine stimulation of osteogenic PCa metastasis. Inhibitors of PSA enzymatic activity could be useful therapeutic agents.
Gygi
Christian M
CM
Lilly Research Laboratories, Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Leibovitch
Ilan Y
IY
Adlington
Robert
R
Baldwin
Jack E
JE
Chen
Beining
B
Mccoull
William
W
Pritchard
Gareth J
GJ
Becker
Gerald W
GW
Dixon
Eric P
EP
Little
Sheila P
SP
Sutkowski
Debra M
DM
Teater
Carroll
C
Neubauer
Blake Lee
BL
D000293:Adolescent; D001565:Benzoates / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007769:Lactams / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013739:Testosterone / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology; D014407:Tumor Cells, Cultured
D001565:Benzoates; C471184:LY 312340; D007769:Lactams; D013739:Testosterone; D017430:Prostate-Specific Antigen