Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.
OBJECTIVE
Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells.


METHODS
Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed.


RESULTS
Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines.


CONCLUSIONS
These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome.
Department of Medical Oncology, University of Thessaly School of Medicine, Larissa, Greece.
Konstantinos
K
Tsapakidis
Panagiotis J
PJ
Vlachostergios
Ioannis A
IA
Voutsadakis
Christina D
CD
Befani
Anna
A
Patrikidou
Eleana
E
Hatzidaki
Danai D
DD
Daliani
George
G
Moutzouris
Panagiotis
P
Liakos
Christos N
CN
Papandreou
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001839:Bombesin / Q000187:drug effects* / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D019332:Endothelin-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects / Q000235:genetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014178:Translocation, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics; D051025:bcl-Associated Death Protein / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; C494819:BAD protein, human; D001897:Boronic Acids; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019332:Endothelin-1; D016209:Interleukin-8; D016328:NF-kappa B; D011719:Pyrazines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D051025:bcl-Associated Death Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069286:Bortezomib; D020928:Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D001839:Bombesin