Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer death in men in the US. Recent studies demonstrated that prostate cancer cells grow in a chronic or transient hypoxic microenvironment. A correlation between the extent of tumor hypoxia and poor clinical outcome has also been demonstrated. More recently, androgen deprivation, the most common form of prostate cancer therapy, was itself shown to generate a state of transient hypoxia in prostate cancer. Two highly homologous members of the peroxiredoxin protein family, Prx1 and Prx2, have been shown to affect cell proliferation/apoptosis and increase the stress resistance in cancer cells. However, the effects of Prx expression in human cancers, their influence on cancer therapy, and the regulatory basis of their expression in cancer have not been investigated. Because these Prxs can be predicted to have a significant impact on prostate cancer, the investigator has recently undertaken studies of Prx1/2 in prostate cancer. The research proposed in this application emanates from our recent studies of Prx1/2 regulation and function in human prostate cancer cells and tissues. The observations made in the Pi's laboratory led us to postulate that Prx1 possesses unique functions and regulatory mechanisms in human prostate cancer that significantly influences its malignant progression. Our preliminary data described herein provide compelling support of this prediction. It is hypothesized that hypoxia-induced oxidative stress in tumors up-regulates Prx1 expression via activating the redox-sensitive transcriptional factors and signaling molecules and that the dysregulated activation of these regulatory components leads to a constitutive Prx1 elevation in a subset of cancer cells. It is also hypothesized that the elevated Prx1 in these cells provides them with aggressive survival phenotypes, in part by directly reducing ROS and oxidative damage, and also by increasing prostate specific antigen (PSA) expression and androgen receptor (AR) activity. It is further hypothesized that the functions of Prx1 are mediated by its ability to control the oxidation/function of redox-sensitive molecules that in turn contribute to the malignant progression of prostate cancer.
Three Specific Aims are proposed to test these hypotheses.
In Aim 1, we will establish the molecular basis for Prx1 elevation in human prostate cancer cells.
In Aim 2, we will determine the functional significance of Prx1 in malignant progression of prostate cancer cells. In particular, we will investigate the novel role for Prx1 in regulating PSA expression and AR activity in response to hypoxia.
In Aim 3, we will identify important redox-sensitive target/effecter molecules that mediate the Prx1 functions to promote malignant progression of prostate cancer. The objective of the proposed research is to define the role of Prx1 in hypoxia-response of prostate cancer and the underlying regulatory mechanisms involved. This study will also provide a sound scientific basis upon which the role of Prx1 can be elucidated in prostate cancer, enabling the development of novel prognostic/therapeutic approaches to inhibit its malignant progression. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA111846-01A2
Application #
7101594
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Sussman, Daniel J
Project Start
2006-04-05
Project End
2011-02-28
Budget Start
2006-04-05
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$308,289
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Riddell, Jonah R; Bshara, Wiam; Moser, Michael T et al. (2011) Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4-dependent regulation of tumor vasculature. Cancer Res 71:1637-46
Riddell, Jonah R; Wang, Xiang-Yang; Minderman, Hans et al. (2010) Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4. J Immunol 184:1022-30
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Park, Soo-Yeon; Yu, Xiaofei; Ip, Clement et al. (2007) Peroxiredoxin 1 interacts with androgen receptor and enhances its transactivation. Cancer Res 67:9294-303
Kim, Joo-Heon; Bogner, Paul N; Ramnath, Nithya et al. (2007) Elevated peroxiredoxin 1, but not NF-E2-related factor 2, is an independent prognostic factor for disease recurrence and reduced survival in stage I non-small cell lung cancer. Clin Cancer Res 13:3875-82
Lee, Weonsup; Choi, Kyoung-Soo; Riddell, Jonah et al. (2007) Human peroxiredoxin 1 and 2 are not duplicate proteins: the unique presence of CYS83 in Prx1 underscores the structural and functional differences between Prx1 and Prx2. J Biol Chem 282:22011-22
Kim, Yun-Jeong; Lee, Weon-Sup; Ip, Clement et al. (2006) Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex. Cancer Res 66:7136-42
Choi, Kyoung-Soo; Park, Soo-Yeon; Baek, Sun-Hee et al. (2006) Analysis of protein redox modification by hypoxia. Prep Biochem Biotechnol 36:65-79

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