Hypoxia is a key regulatory microenvironmental factor capable of influencing tumor development andprogression. Hypoxia is usually considered a global phenomenon, defined as an overall reduced oxygenavailability or partial pressure below critical levels. Tumor vasculature, however, is architecturally andfunctionally abnormal. The tissue oxygenation/blood flow within a tumor is dynamically changing andheterogeneous at the microenvironmental level. Hypoxia has been proposed to functions as amicroenvironmental pressure to select for a fraction of hypoxia-resistant cancer cells with an increased abilityto survive and progress. Peroxiredoxins(Prxs) are a newly described family of redox-controlling proteins. Two highly homologous members of this protein family, Prx1 and Prx2, have been shown to affect cell survival andincrease stress resistance. However, little is known about the effects of Prx elevation in human cancers, theirinfluence on malignant progression and treatment response, or the regulatory mechanisms. Our preliminarystudies provide compelling evidences to support the functional relevance of hypoxiaand Prx1 (but not Prx2) inenhancing the AR function, and suppressing apoptotic signaling. In this study, we will systematicallyinvestigate 'why'and 'how' Prx1 is elevate in prostate cancer cells at the microenvironmentallevel, and studythe effect of tissue oxygenation status and Prx1level in modifying the cancer control efficacy of finasteride andselenium. We hypothesize that dynamic changes of tissue oxygenation up-regulate Prx1 expression viaredox-sensitive transcription factors, and the dysregulated activation of these transcription factors leads to Prx1 elevation in a subset of prostate cells within a tumor. We also hypothesize that elevated Prx1 confers anaggressive survival phenotype to cells by enhancing AR activity, and reducing oxidative damage andapoptosis. We correspondingly hypothesize that inhibition of Prx1 will increase the AR signaling suppressiveand cancer control efficacy of finasteride and selenium. In order to test these hypotheses, four specific aimsare proposed.
In Aim 1, we will define the molecular basis of Prx1 up-regulation in prostate cancer cells.
In Aim 2, we will elucidate the mechanisms whereby Prx1 enhances AR function.
In Aim 3 and Aim 4, we willsystematically investigate whether and how Prx1 modifies the cancer control efficacy of finasteride andselenium in the context of a hypoxic tumor microenvironment. These studies will provide a sound scientificbasis upon which the regulation and function of Prx1 can be elucidated in prostate cancer, enabling thedevelopment of novel preventive approaches to inhibit its malignant progression.
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