Current Search:   Ottman, Richard (x)

View All Items

  • CSV Spreadsheet
(1 - 2 of 2)
Involvement of miRNAs in the Development of Androgen Independent Prostate Cancer
Title
Involvement of miRNAs in the Development of Androgen Independent Prostate Cancer.
Creator
Ottman, Richard, Chakrabarti, Ratna, Cole, Alexander, Khaled, Annette, Zervos, Antonis, University of Central Florida
Abstract / Description
Development of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially result in tumor regression but development of compensatory mechanisms including AR bypass signaling leads to tumor re-growth, independent of circulating androgens. The result is the emergence of castration resistant prostate cancer (CRPC), a highly morbid disease exhibiting...
Show moreDevelopment of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially result in tumor regression but development of compensatory mechanisms including AR bypass signaling leads to tumor re-growth, independent of circulating androgens. The result is the emergence of castration resistant prostate cancer (CRPC), a highly morbid disease exhibiting aberrant expression of many protein-coding and non-coding genes. Under the umbrella of non-coding RNAs is a class of small regulatory RNAs referred to as microRNAs (miRNAs). MicroRNAs are believed to function in the maintenance of cell homeostasis but are often differentially expressed in many different types of cancer including CRPC.In this study, the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT was determined. Androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX were used. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. A correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells was shown.Additionally, profiles of miRNA expressions in cancerous prostate tissues were created and compared with profiles of paired adjacent uninvolved areas of prostate tissue. Among the miRNAs identified from these analyses, a cluster of miRNAs, miR-17-92a, that is under-expressed in prostate tumors and in androgen independent prostate cancer cells was highlighted. The miR-17-92a cluster miRNAs are transcribed from a polycistronic transcription unit C13orf25 that generates six mature miRNAs: miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a, and is commonly de-regulated in many cancers. In this research, the expression of miR-17-92a miRNAs was found to be reduced in cancerous prostate tissues when compared to uninvolved areas and also in aggressive prostate cancer cells. Restoration of expression of all members of miR-17-92a cluster showed decreased expression of cell cycle regulatory proteins cyclin D1 and SSH1; as well as LIMK1 and FGD4 of the RhoGTPase signaling pathway. Expression of miR-17-92a miRNAs caused decreased cell proliferation, reduced activation of AKT and MAP kinases, delayed tumorigenicity and reduced tumor growth in animals. Additionally, miR-17-92a miRNA expression inhibited EMT via reduced cell migration and expression of mesenchymal markers while elevating expression and surface localization of the epithelial marker e-cadherin. Expression of miR-17-92a miRNAs improved sensitivity of androgen dependent LNCaP104-S prostate cancer cells to the Androgen Receptor antagonist bicalutamide (CDX), AKT inhibitor MK-2206 2HCl, and docetaxel. Androgen refractory PC-3 cells also showed increased sensitivity to docetaxel, MK-2206 2HCl, and Aurora kinase inhibitor VX680 upon ectopic expression of miR-17-92a cluster miRNAs. In conclusion, dynamic alterations in miRNA expression occur early on during androgen deprivation therapy and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Notably, these data demonstrate a tumor suppressor effect of miR-17-92a cluster miRNAs in prostate cancer cells and restoration of expression of these miRNAs has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells. Furthermore, these results can be used as a prognostic marker of cancers with a potential to be resistant to ADT.
Show less
Date Issued
2016
Identifier
CFE0006697, ucf:52866
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006697
LIMK1 Promotes MT1-MMP Expression and Localization to the Plasma Membrane
Title
LIMK1 Promotes MT1-MMP Expression and Localization to the Plasma Membrane.
Creator
Ottman, Richard, Chakrabarti, Ratna, Cole, Alexander, Zervos, Antonis, University of Central Florida
Abstract / Description
LIM Kinase 1 (LIMK1), a serine/threonine kinase, modulates actin polymerization and microtubule assembly. The function of LIMK1 is regulated by kinases that are activated by Rho and Rac GTPases. LIMK1 is overexpressed in various cancerous cell types and tissues and its overexpression promotes increased invasion and metastasis of breast and prostate cancer cells. The Membrane-Type Matrix Metalloproteinase 1 (MT1-MMP) is a member of the zinc-binding collagenase family, which is involved in...
Show moreLIM Kinase 1 (LIMK1), a serine/threonine kinase, modulates actin polymerization and microtubule assembly. The function of LIMK1 is regulated by kinases that are activated by Rho and Rac GTPases. LIMK1 is overexpressed in various cancerous cell types and tissues and its overexpression promotes increased invasion and metastasis of breast and prostate cancer cells. The Membrane-Type Matrix Metalloproteinase 1 (MT1-MMP) is a member of the zinc-binding collagenase family, which is involved in extracellular matrix breakdown and activation of secreted MMP-2. The balance between activation and inhibition of MT1-MMP and MMP-2 helps maintaining normal extracellular matrix turnover. However, it has been shown that elevated MT1-MMP expression can cause excessive ECM digestion and promote tumor invasion and metastasis. Since RhoA and Rac1 have been implicated in metastasis and invasion along with LIMK1 activation, we investigated a possible link between LIMK1 and MT1-MMP. Our results show that the level of MT1-MMP expression is correlated with that of LIMK1 and LIMK1 acts as a transcriptional regulator of MT1-MMP. Additionally, we show that LIMK1 physically associates with MT1-MMP and promotes its translocation to the plasma membrane.
Show less
Date Issued
2012
Identifier
CFE0004581, ucf:49208
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0004581