| Abstract |
The main property of cancer cells is to proliferate and expand by limiting cell death. This procedure involves the receptiveness of tumor to its microenviroment and the use of growth factors and hormonal components. Prostate cancer consists a classical hormone-dependent cancer while for colon cancer not such association is well established. We have recently shown that androgen steroid Testosterone exerts pro-apoptotic effects in both cancer types through a rapid, membrane-initiated mechanism. In addition, we have recently described that another androgen, Dehydroepiandrosterone (DHEA) can activate Nerve Growth Factor receptors, namely TrkA and p75NTR in neural cells. NGF as a growth factor has been shown to participate in cancer cells proliferation and migration. Recent data show that NGF receptors, TrkA and p75NTR play important role in cancer, exerting pleiotropic effects in proliferation, migration or apoptosis of cancer cells.
In the present study, we evaluated the effects of androgens, Testosterone and DHEA that are key players for the development of prostate cancer, in the NGF receptors-mediated regulation of apoptosis in prostate but also colon cancer cells. Specifically, we investigated the effects of Testosterone and DHEA in apoptosis of prostate cancer cell lines, DU145 and LNCaP and the colon cancer cell line CaCO2.
Conclusively, our results show that DHEA and NGF strongly reversed serum-deprivation-induced apoptosis while Testosterone induces cell apoptosis in the presence of serum of all cancer cell lines. The anti-apoptotic effect of both DHEA and NGF was completely reversed after priming of the cells with Testosterone. We also indicate that all cancer cell lines of prostate (DU145 and LNCaP) and colon (CaCO2) express both of the NGF receptors, namely TrkA and p75NTR and also we show that Testosterone treatment reduces the expression of TrkA receptor while DHEA and NGF increase receptor’s expression. The effects of androgens were abolished in both cell lines in the presence of TrkA inhibitor. The use of p75NTR inhibitor had different effects on prostate versus colon cancer, specifically in prostate cell line DU145, the anti-apoptotic effect of DHEA and NGF was significantly decreased in the presence of the inhibitor, while in colon cancer cell line CaCO2, the protective effect of DHEA was similar compared to the absence of the inhibitor. Finally, we tested the functional effects of Testosterone and DHEA in the activation of TrkA and p75NTR receptors. DHEA, as NGF, induces the phosphorylation of TrkA and interaction of the p75NTR receptor with intracellular molecules like RhoGDI and RIP2, while Testosterone did not show any ability to activate neither TrkA nor p75NTR receptors.
Our findings suggest that the interplay between steroid hormone and neurotrophins signaling in hormone-dependent tumors offers new insights in the pathophysiology of these neoplasias.
|
Διερεύνηση των αλληλεπιδράσεων ανδρογόνων ορμονών με την οικογένεια των υποδοχέων του νευρικού αυξητικού παράγοντα στην ρύθμιση της αποπτωτικής δράσης τους στον καρκίνο του προστάτη και του παχέως εντέρου
