title: Differential effects of dehydroepiandrosterone and testosterone in prostate and colon cancer cell apoptosis: the role of nerve growth factor (NGF) receptors.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Crete Medical School, GR-71003 Heraklion, Greece.
authors.forename: Vasileia
authors.initials: V
authors.lastname: Anagnostopoulou
authors.forename: Iosif
authors.initials: I
authors.lastname: Pediaditakis
authors.forename: Saad
authors.initials: S
authors.lastname: Alkahtani
authors.forename: Saud A
authors.initials: SA
authors.lastname: Alarifi
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schmidt
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D013739:Testosterone; D003687:Dehydroepiandrosterone; D020932:Nerve Growth Factor