Search Results

You are looking at 1 - 2 of 2 items for

  • Author: Lirim Shemshedini x
Clear All Modify Search
Prabesh Khatiwada Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA
Center for Translational Immunology, Columbia University, New York, New York, USA

Search for other papers by Prabesh Khatiwada in
Google Scholar
PubMed
Close
,
Ujjwal Rimal Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

Search for other papers by Ujjwal Rimal in
Google Scholar
PubMed
Close
,
Zhengyang Han Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA
Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts, USA

Search for other papers by Zhengyang Han in
Google Scholar
PubMed
Close
, and
Lirim Shemshedini Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

Search for other papers by Lirim Shemshedini in
Google Scholar
PubMed
Close

Androgen receptor (AR) and its constitutively active splice variant, AR Variant 7 (AR-V7), regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by the ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrate that the interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to a reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.

Open access
Prabesh Khatiwada Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA
Center for Translational Immunology, Columbia University, New York, NY, USA

Search for other papers by Prabesh Khatiwada in
Google Scholar
PubMed
Close
,
Ujjwal Rimal Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

Search for other papers by Ujjwal Rimal in
Google Scholar
PubMed
Close
,
Mamata Malla Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

Search for other papers by Mamata Malla in
Google Scholar
PubMed
Close
,
Zhengyang Han Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

Search for other papers by Zhengyang Han in
Google Scholar
PubMed
Close
, and
Lirim Shemshedini Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

Search for other papers by Lirim Shemshedini in
Google Scholar
PubMed
Close

Androgen receptor (AR) plays a vital role in the development and progression of prostate cancer from the primary stage to the usually lethal stage known as castration-resistant prostate cancer (CRPC). Constitutively active AR splice variants (AR-Vs) lacking the ligand-binding domain are partially responsible for the abnormal activation of AR and may be involved in resistance to AR-targeting drugs occurring in CRPC. There is increasing consensus on the potential of drugs targeting protein–protein interactions. Our lab has recently identified transmembrane 4 superfamily 3 (TM4SF3) as a critical interacting partner for AR and AR-V7 and mapped the minimal interaction regions. Thus, we hypothesized that these interaction domains can be used to design peptides that can disrupt the AR/TM4SF3 interaction and kill prostate cancer cells. Peptides TA1 and AT1 were designed based on the TM3SF3 or AR interaction domain, respectively. TA1 or AT1 was able to decrease AR/TM4SF3 protein interaction and protein stability. Peptide TA1 reduced the recruitment of AR and TM4SF3 to promoters of androgen-regulated genes and subsequent activation of these AR target genes. Peptides TA1 and AT1 were strongly cytotoxic to prostate cancer cells that express AR and/or AR-V7. Peptide TA1 inhibited the growth and induced apoptosis of both enzalutamide-sensitive and importantly enzalutamide-resistant prostate cancer cells. TA1 also blocked the migration and malignant transformation of prostate cancer cells. Our data clearly demonstrate that using peptides to target the important interaction AR has with TM4SF3 provides a novel method to kill enzalutamide-resistant prostate cancer cells that can potentially lead to new more effective therapy for CRPC.

Open access