Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells
Article first published online: 16 MAY 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 73, Issue 1, pages 23–30, January 2013
How to Cite
Golovine, K. V., Makhov, P. B., Teper, E., Kutikov, A., Canter, D., Uzzo, R. G. and Kolenko, V. M. (2013), Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells. Prostate, 73: 23–30. doi: 10.1002/pros.22535
- Issue published online: 29 NOV 2012
- Article first published online: 16 MAY 2012
- Manuscript Accepted: 18 APR 2012
- Manuscript Received: 2 DEC 2011
- The National Institutes of Health Grants. Grant Numbers: RO1 CA134463, CCSG, P30 CA006927
- The American Institute for Cancer Research Grant. Grant Number: 09A023
- The Department of Defense Physician Research Training Award. Grant Number: W81XWH-10-1-0187
- androgen receptor;
- prostate cancer
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.
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-H2DCFDA, followed by flow cytometry analysis.
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.
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.