Specialty potato extract and its anthocyanin fraction induce caspase‐independent apoptosis by nuclear translocation of apoptosis inducing factor (AIF) and Endonuclease G (Endo G) in prostate cancer cells

2007 ◽  
Vol 21 (5) ◽  
Author(s):  
L. Reddivari ◽  
J. Vanamala ◽  
S.H. Safe ◽  
J.C. Miller
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Prostate Cancer Cells ◽  
Endonuclease G ◽  
Potato Extract ◽  
Apoptosis Inducing Factor

scholarly journals PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 3
Author(s):  
Magali Williamson ◽  
Ritu Garg ◽  
Claire M. Wells
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
Cancer Cells ◽  
Androgen Deprivation Therapy ◽  
Late Stage ◽  
Nuclear Translocation ◽  
Androgen Deprivation ◽  
Nuclear Localization Sequence ◽  
Prostate Cancer Cells ◽  
Localization Sequence

Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), the mainstay of treatment for late stage prostate cancer. PlexinB1, a receptor for semaphorins, has been implicated in various cancers including prostate cancer and has a role in resistance to ADT. We show here that activation of PlexinB1 by Sema4D and Sema3C results in translocation of endogenous GR to the nucleus in prostate cancer cells, and that this effect is dependent on PlexinB1 expression. Sema4D/Sema3C promotes the translocation of GR-GFP to the nucleus and mutation of the nuclear localization sequence (NLS1) of GR abrogates this response. These findings implicate the importin α/β system in the Sema4D/Sema3C-mediated nuclear import of GR. Knockdown of PlexinB1 in prostate cancer cells decreases the levels of glucocorticoid-responsive gene products and antagonizes the decrease in cell motility and cell area of prostate cancer cells upon dexamethasone treatment, demonstrating the functional significance of these findings. These results show that PlexinB1 activation has a role in the trafficking and activation of the nuclear receptor GR and thus may have a role in resistance to androgen deprivation therapy in late stage prostate cancer.

scholarly journals Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 711 ◽  
Author(s):  
Haneen Amawi ◽  
Noor Hussein ◽  
Sai H. S. Boddu ◽  
Chandrabose Karthikeyan ◽  
Frederick E. Williams ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Wide Spectrum ◽  
Thiophene Ring ◽  
Mitotic Catastrophe ◽  
Prostate Cancer Cells

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.

Identification of a small-molecule inhibitor of Stat5a/b through structure-based screen for therapy development for prostate cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 17-17
Author(s):  
Z. Liao ◽  
L. Gu ◽  
F. Shen ◽  
A. Dagvadorj ◽  
S. Gupta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Nuclear Translocation ◽  
Human Prostate ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Molecule Inhibitor ◽  
Prostate Cancers

17 Background: There are no effective treatments for metastatic or castration resistant prostate cancer. We have shown that transcription factor Stat5a/b is constitutively active in high-grade prostate cancer, but not in normal human prostate epithelium. Stat5a/b is active in 95% of clinical castration resistant prostate cancers, and the expression of active Stat5a/b in primary prostate cancer predicts early disease recurrence. Stat5a/b is critical for the viability of prostate cancer cells in vitro and for growth of prostate xenograft tumors in nude mice. Stat5a/b synergizes with androgen receptor (AR) and Stat5a/b promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Here, we hypothesize that Stat5a/b is a molecular target for rational drug design for prostate cancer. Methods: We identified a small- molecule inhibitor of Stat5a/b dimerization by structure-based virtual screen from a database of 30 million chemical structures. The efficacy of the Stat5a/b inhibitor was determined by reporter gene assays, dimerization by co-immunoprecipitations, nuclear translocation by cytochemistry and binding to DNA by EMSA. Cell viability was analyzed by MTT assay. Results: The novel Stat5a/b inhibitor IST5-002 inhibited transcriptional activity of Stat5a/b at IC50 of 1.5 μ M for Stat5a and 3.5 μ M for Stat5b, but not of Stat3 in prostate cancer cells. IST5-002 inhibited dimerization, nuclear translocation, and binding of Stat5a/b to the Stat5 DNA consensus sequence. Furthermore, IST5-002 inhibited expression of Stat5a/b target gene cyclin D1, and induced massive apoptosis of DU145, CWR22Rv1 and LNCaP human prostate cancer cells. IST5-002 blocked prostate cancer xenograft tumor growth in nude mice and induced death in clinical prostate cancers ex vivo in 3D organ cultures. Conclusions: We have identified a small molecule Stat5a/b inhibitor IST5-002 for therapy development for prostate cancer. Future work will focus on chemical modifications of IST5-002 to achieve IC50 below 1 μ M and oral administration. No significant financial relationships to disclose.

scholarly journals The Enzymatic Activity of Apoptosis-inducing Factor Supports Energy Metabolism Benefiting the Growth and Invasiveness of Advanced Prostate Cancer Cells

2012 ◽  
Vol 287 (52) ◽  
pp. 43862-43875 ◽  
Author(s):  
Eric M. Lewis ◽  
Amanda S. Wilkinson ◽  
Jacqueline S. Jackson ◽  
Rohit Mehra ◽  
Sooryanarayana Varambally ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Energy Metabolism ◽  
Enzymatic Activity ◽  
Cancer Cells ◽  
Advanced Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Apoptosis Inducing Factor

Protein Kinase A phosphorylates NCoR to enhance its nuclear translocation and repressive function in human prostate cancer cells

2013 ◽  
Vol 228 (6) ◽  
pp. 1159-1165 ◽  
Author(s):  
Hyo-Kyoung Choi ◽  
Jung-Yoon Yoo ◽  
Mi-Hyeon Jeong ◽  
Soo-Yeon Park ◽  
Dong-Myoung Shin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Kinase A

scholarly journals Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 989
Author(s):  
Priyatham Gorjala ◽  
Rick A. Kittles ◽  
Oscar B. Goodman Jr. ◽  
Ranjana Mitra
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Receptor Signaling ◽  
Wild Type ◽  
Prostate Cancer Cells ◽  
Androgen Receptor Signaling

Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high levels of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression, and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling, and cell growth, whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity as the effects are reduced in the CYP3A5 knockout background. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.

scholarly journals The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

2019 ◽  
Author(s):  
Haneen Amawi ◽  
Noor Hussein ◽  
Sai HS Boddu ◽  
Chandrabose Karthikeyan ◽  
Frederick E. Williams ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Biologically Active ◽  
Beta Catenin ◽  
Lead Compound ◽  
Prostate Cancer Cells

Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50&lt; 1&micro;M). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 &micro;M) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 &micro;M) inhibits the wingless-type MMTV (Wnt)/&beta;-catenin signaling pathway, mainly by inducing &beta;-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 &micro;M) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 &micro;M) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 &micro;M. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

Sign in / Sign up

Export Citation Format

Share Document