Tumor growth is fostered by inhibition of cell death, which involves the receptiveness of
tumor to
growth factors and
hormones. We have recently shown that
testosterone exerts proapoptotic effects in prostate and
colon cancer cells through a membrane-initiated mechanism. In addition, we have recently reported that
dehydroepiandrosterone (
DHEA) can control cell fate, activating
nerve growth factor (
NGF) receptors, namely
tropomyosin-related
kinase (Trk)A and
p75 neurotrophin receptor, in primary neurons and in PC12 tumoral cells.
NGF was recently involved in
cancer cell proliferation and apoptosis. In the present study, we explored the cross talk between
androgens (
testosterone and
DHEA) and
NGF in regulating apoptosis of prostate and
colon cancer cells.
DHEA and
NGF strongly blunted serum deprivation-induced apoptosis, whereas
testosterone induced apoptosis of both
cancer cell lines. The antiapoptotic effect of both
DHEA and
NGF was completely reversed by
testosterone. In line with this,
DHEA or
NGF up-regulated, whereas
testosterone down-regulated, the expression of
TrkA receptor. The effects of
androgens were abolished in both cell lines in the presence of TrkA inhibitor.
DHEA induced the phosphorylation of TrkA and the interaction of
p75 neurotrophin receptor with its effectors, Rho
protein GDP dissociation inhibitor and receptor interacting
serine/threonine-protein kinase 2. Conversely,
testosterone was unable to activate both receptors.
Testosterone acted as a
DHEA and
NGF antagonist, by blocking the activation of both receptors by
DHEA or
NGF. Our findings suggest that
androgens may influence
hormone-sensitive
tumor cells via their cross talk with
NGF receptors. The interplay between
steroid hormone and
neurotrophins signaling in
hormone-dependent
tumors offers new insights in the pathophysiology of these
neoplasias.