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Functional link between the Protein kinase A (PKA) pathway and androgen receptor (AR) in prostate cancer (PCa) and characterization of the AR directed novel therapeutic compounds

Sarwar, Martuza (2013) MOBT15 20112
Degree Projects in Molecular Biology
Abstract
Cellular signalling and potential agents to combat prostate cancer

Prostate cancer (PCa) arises as a result of uncontrolled proliferation of the cells in the male prostate gland. The male androgenic hormone, testosterone fuels prostate cancer cells. In the cells of the prostate, the androgen receptor (AR) acts as the signal receiver and effector of androgen, ultimately leading to the growth and survival of cancer cells upon binding and activated by androgen. Thus the most effective approach adopted by clinicians is to diminish the signal (andogen levels) with castration or blocking the effector (AR) with molecules termed as antiandrogens. However, the disease often becomes resistant to castration, called castration resistant prostate... (More)
Cellular signalling and potential agents to combat prostate cancer

Prostate cancer (PCa) arises as a result of uncontrolled proliferation of the cells in the male prostate gland. The male androgenic hormone, testosterone fuels prostate cancer cells. In the cells of the prostate, the androgen receptor (AR) acts as the signal receiver and effector of androgen, ultimately leading to the growth and survival of cancer cells upon binding and activated by androgen. Thus the most effective approach adopted by clinicians is to diminish the signal (andogen levels) with castration or blocking the effector (AR) with molecules termed as antiandrogens. However, the disease often becomes resistant to castration, called castration resistant prostate cancer (CRPC). It is suggested that, the AR becomes hypersensitive and may be activated by other signaling molecules such as the cyclic adenosine monophosphate (cAMP) in CRPC.
In the first part of this project, we wanted to define clinical importance and correlation between AR and protein kinase A or PKA (a protein that acts as the receiver and effectors of cAMP) during the progression of PCa. By analyzing the gene expression of patient samples, we showed that there are significant correlation between AR and PKA. When we increased the cAMP level in LNCaP cells (a well well-known cell line closely mimicking human PCa) in the laboratory, AR was increased to the similar level as low level (5nM) of androgen. Interestingly, androgen treatment alone showed significant increase of PKA proteins along with AR, indicating a direct link between AR and PKA. Our study provides new information and raised the possibility of future studies to investigate the different aspects of PKA in PCa.
Aggressive forms of cancer, in particular CRPCs that have already spread to different parts of the body remain a major clinical challenge, as they response poorly to therapy and become resistant to most of the available medications. Therefore there is an urgent need to develop novel therapies to target PCa. In the second part of the project, we evaluated and identified the possible mechanism of action of a novel chemotherapeutic compound in the laboratory. Our result showed that treatment of the novel compound in LNCaP leads to the reduction of AR protein along its target gene PSA. We also revealed that treatment in LNCaP cells led to the inhibition of phospho AKT (activated AKT) with immunofluorescence and immunoblott analysis. Furthermore, treatment with the novel compound also kills the PCa cells as shown by the presence of apoptotic bodies with our fluorescence microscopic analysis. Our data indicates the potential utility of the novel chemotherapeutic compound for prostate cancer. However more studies are required for better characterization as well as we need to identify the exact target of the novel compound.

Advisor: Assoc. Prof. Dr. Jenny L Persson
Degree project 60 credits in Cell and Molecular Biology, 2013
Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Sarwar, Martuza
supervisor
organization
course
MOBT15 20112
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
3514332
date added to LUP
2013-02-20 14:02:47
date last changed
2013-02-20 14:02:47
@misc{3514332,
  abstract     = {Cellular signalling and potential agents to combat prostate cancer

Prostate cancer (PCa) arises as a result of uncontrolled proliferation of the cells in the male prostate gland. The male androgenic hormone, testosterone fuels prostate cancer cells. In the cells of the prostate, the androgen receptor (AR) acts as the signal receiver and effector of androgen, ultimately leading to the growth and survival of cancer cells upon binding and activated by androgen. Thus the most effective approach adopted by clinicians is to diminish the signal (andogen levels) with castration or blocking the effector (AR) with molecules termed as antiandrogens. However, the disease often becomes resistant to castration, called castration resistant prostate cancer (CRPC). It is suggested that, the AR becomes hypersensitive and may be activated by other signaling molecules such as the cyclic adenosine monophosphate (cAMP) in CRPC.
In the first part of this project, we wanted to define clinical importance and correlation between AR and protein kinase A or PKA (a protein that acts as the receiver and effectors of cAMP) during the progression of PCa. By analyzing the gene expression of patient samples, we showed that there are significant correlation between AR and PKA. When we increased the cAMP level in LNCaP cells (a well well-known cell line closely mimicking human PCa) in the laboratory, AR was increased to the similar level as low level (5nM) of androgen. Interestingly, androgen treatment alone showed significant increase of PKA proteins along with AR, indicating a direct link between AR and PKA. Our study provides new information and raised the possibility of future studies to investigate the different aspects of PKA in PCa.
Aggressive forms of cancer, in particular CRPCs that have already spread to different parts of the body remain a major clinical challenge, as they response poorly to therapy and become resistant to most of the available medications. Therefore there is an urgent need to develop novel therapies to target PCa. In the second part of the project, we evaluated and identified the possible mechanism of action of a novel chemotherapeutic compound in the laboratory. Our result showed that treatment of the novel compound in LNCaP leads to the reduction of AR protein along its target gene PSA. We also revealed that treatment in LNCaP cells led to the inhibition of phospho AKT (activated AKT) with immunofluorescence and immunoblott analysis. Furthermore, treatment with the novel compound also kills the PCa cells as shown by the presence of apoptotic bodies with our fluorescence microscopic analysis. Our data indicates the potential utility of the novel chemotherapeutic compound for prostate cancer. However more studies are required for better characterization as well as we need to identify the exact target of the novel compound.

Advisor: Assoc. Prof. Dr. Jenny L Persson
Degree project 60 credits in Cell and Molecular Biology, 2013
Department of Biology, Lund University},
  author       = {Sarwar, Martuza},
  language     = {eng},
  note         = {Student Paper},
  title        = {Functional link between the Protein kinase A (PKA) pathway and androgen receptor (AR) in prostate cancer (PCa) and characterization of the AR directed novel therapeutic compounds},
  year         = {2013},
}