Journal article
KN-93 inhibits androgen receptor activity and induces cell death irrespective of p53 and Akt status in prostate cancer
Cancer biology & therapy, Vol.9(3), pp.223-234
02/01/2010
DOI: 10.4161/cbt.9.3.10747
PMID: 20023417
Abstract
It has been suggested that the downregulation of AR expression should be considered the principal strategy for the treatment of hormone-refractory prostate cancer. We have previously shown that inhibition of AR induced PI3K-independent activation of Akt that was mediated by CaMKII. In this study, we found that the CaMKII inhibitor KN-93 has a broader effect on apoptosis than just inhibition of CaMKII: first, KN-93 inhibits AR activity and induces cell death in PCa cells after androgen deprivation when many other drugs fail to kill prostate cancer cells; second, KN-93 inhibits expression of the anti-apoptotic protein Mcl-1 and induces expression of the pro-apoptotic protein PUMA; third, KN-93-mediated cell death is p53-independent; and fourth, KN-93 induces the generation of ROS. The ROS induction allows KN-93 to circumvent the activation of Akt, which occurs in prostate cancer cells under androgen deprivation, since Akt could not inhibit ROS-mediated apoptosis. KN-93 also synergistically induces cell death in combination with low doses of doxorubicin and converts the phenotype of prostate cancer cells from TRAIL-resistant to -sensitive. These data suggest that KN-93 could be used for novel therapeutic approaches when hormonal therapy has failed.
Details
- Title: Subtitle
- KN-93 inhibits androgen receptor activity and induces cell death irrespective of p53 and Akt status in prostate cancer
- Creators
- Oskar W. Rokhlin - University of IowaNatalya V. Guseva - University of IowaAgshin F. Taghiyev - University of IowaRebecca A. Glover - University of IowaMichael B. Cohen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancer biology & therapy, Vol.9(3), pp.223-234
- Publisher
- Taylor & Francis
- DOI
- 10.4161/cbt.9.3.10747
- PMID
- 20023417
- ISSN
- 1538-4047
- eISSN
- 1555-8576
- Number of pages
- 12
- Grant note
- Department of Pathology, the University of Iowa, Iowa City
- Language
- English
- Date published
- 02/01/2010
- Academic Unit
- Pathology; Biology
- Record Identifier
- 9984647059402771
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