Activin receptor signaling regulates prostatic epithelial cell adhesion and viability.
Mutational changes coupled with endocrine, paracrine, and/or autocrine signals regulate cell division during carcinogenesis. The hormone signals remain undefined, although the absolute requirement in vitro for fetal serum indicates the necessity for a fetal serum factor(s) in cell proliferation. Using prostatic cancer cell (PCC) lines as a model of cancer cell proliferation, we have identified the fetal serum component activin A and its signaling through the activin receptor type II (ActRII), as necessary, although not sufficient, for PCC proliferation. Activin A induced Smad2 phosphorylation and PCC proliferation, but only in the presence of fetal bovine serum (FBS). Conversely, activin A antibodies and inhibin A suppressed FBS-induced PCC proliferation confirming activin A as one of multiple serum components required for PCC proliferation. Basic fibroblast growth factor was subsequently shown to synergize activin A-induced PCC proliferation. Inhibition of ActRII signaling using a blocking antibody or antisense-P decreased mature ActRII expression, Smad2 phosphorylation, and the apparent viability of PCCs and neuroblastoma cells grown in FBS. Suppression of ActRII signaling in PCC and neuroblastoma cells did not induce apoptosis as indicated by the ratio of active/inactive caspase 3 but did correlate with increased cell detachment and ADAM-15 expression, a disintegrin whose expression is strongly correlated with prostatic metastasis. These findings indicate that ActRII signaling is required for PCC and neuroblastoma cell viability, with ActRII mediating cell fate via the regulation of cell adhesion. That ActRII signaling governs both cell viability and cell adhesion has important implications for developing therapeutic strategies to regulate cancer growth and metastasis.
Simon
Derek P
DP
Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin, Veterans Administration Hospital, Madison, WI 53705, USA.
Vadakkadath Meethal
Sivan
S
Wilson
Andrea C
AC
Gallego
Miguel J
MJ
Weinecke
Stephanie L
SL
Bruce
Erin
E
Lyons
Patrick F
PF
Haasl
Ryan J
RJ
Bowen
Richard L
RL
Atwood
Craig S
CS
D051722:ADAM Proteins / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism*; D028341:Activins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D008565:Membrane Proteins; C422405:activin A; D028341:Activins; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; D051722:ADAM Proteins; C098660:ADAM15 protein, human