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Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells
Author(s) -
Golovine Konstantin V.,
Makhov Peter B.,
Teper Ervin,
Kutikov Alexander,
Canter Daniel,
Uzzo Robert G.,
Kolenko Vladimir M.
Publication year - 2013
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22535
Subject(s) - androgen receptor , prostate cancer , flow cytometry , cancer research , carcinogenesis , cell growth , chemistry , reactive oxygen species , cancer cell , biology , microbiology and biotechnology , cancer , medicine , biochemistry
BACKGROUND Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis, and its modulation represents a logical target for prostate cancer (PC) prevention and treatment. Natural products are the most consistent source of small molecules for drug development. In this study, we investigate the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum), on AR expression in PC cells and delineate its mechanism of action. METHODS Expression and transcriptional activity of AR was examined by western blotting and luciferase reporter assay, respectively. CellTiter Blue assay was utilized to quantify cell proliferation. Reactive oxygen species (ROS) generation was examined by staining cells with a ROS indicator CM‐H 2 DCFDA, followed by flow cytometry analysis. RESULTS The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome‐mediated ROS‐dependent mechanism. Moreover, PL effectively depletes a modified AR lacking the ligand‐binding domain, shedding light on a new paradigm in the treatment approach to prostatic carcinoma that expresses mutated constitutively active AR. Importantly, PL effectively depletes AR in PC cells at low micromolar concentrations, while concurrently exerting a significant inhibitory effect on AR transcriptional activity and proliferation of PC cells. CONCLUSIONS Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in PC cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy. Prostate 73: 23–30, 2013. © 2012 Wiley Periodicals, Inc.