Prostate cancer (PCa) is an increasingly common malignancy worldwide; progression to advanced cancer is highly unpredictable, resulting in a need for new clinically relevant biomarkers or diagnosis tools. A better understanding of PCa pathologic progression would allow development of more sensitive and specific biomarkers. Based on preliminary results from analyses of human PCa tissues, oxidized redox state and posttranslational modification of thioredoxin 1 (Trx1) protein levels were significantly increased in primary PCa with high Gleason scores and metastatic PCa in comparison to adjacent benign tissues. We hypothesize that increased oxidized redox state is contributed to redox imbalance in PCa, leading to increased production of reactive oxygen species/reactive nitrogen species, oxidative DNA damage, mutation of tumor suppressor genes, epigenetic changes, and subsequent PCa progression. To fully understand the relationship of oxidized redox state and PCa progression, a first step involves determining the correlation of oxidized redox state with PCa progression in patient samples.
In Specific Aim 1, human PCa-tumor microarrays with different pathological stages will be constructed, stained with oxidative damage products and analyzed using Vectra/Nuance system. Additionally, thiol redox couples will be measured in human prostate frozen tissues with different pathological stages compared to adjacent benign epithelial prostate tissues. Defining the redox state of PCa and its correlation with disease stage is a necessary first step to determine 1) if oxidized redox state may potentially be used as biomarker for PCa diagnosis and 2) whether oxidized redox state is the cause or consequence of PCa progression. Biochemical analyses of redox state in Aim 1 are time-and labor-intensive and require a large amount of tissues. To overcome these problems, Specific Aim 2 will evaluate if TEMPOL-enhanced MRI could potentially be used in the diagnosis of intracellular redox state of prostate cancer in vivo. TEMPOL can undergo oxidation to the corresponding oxoammonium cation by variant oxidants and its paramagnetism property can be captured by MRI. Oxidizing tissues will exhibit longer-lived MRI signal than reducing tissues. We will scan nude mice with orthotopic xenograft transplant LNCaP-luc-M6 or PC3M-luc-C6 cells to evaluate the possibility and validity of TEMPOL-enhanced MRI. To our knowledge, the present proposal will be the first to 1) attempting correlate tissue redox status with the aggressiveness of PCa in patient samples and 2) use cutting edge technique, TEMPOL enhanced MRI to visualize redox state and diagnosis of PCa. Upon completion of these studies, a better understanding of PCa pathologic/metabolic progression may allow development of more sensitive, more relevant, and more specific biomarkers for early prediction or prognosis of those patients destined for clinical cancer progression.
This project is relevant to public health because prostate cancer (PCa) primarily affects men and is the second leading cause of cancer deaths in males in the US. Since most PCa mortality results from metastases to the bone, more effective diagnosis tool and treatment of metastases is crucial. Defining intracellular redox state (reduction/oxidation) would aid in understanding the pathological process of PCa and may lead to potentially new biomarkers that possibly be used to differentiate benign prostate tissue from less aggressive or from highly aggressive prostate cancer. Thus, developing non-invasive method for accuracy determination of intracellular redox state in prostate cancer in vivo, herein TEMPOL-enhanced MRI, is an important step toward developing redox state as a new biomarker for aggressiveness/metastatic prostate cancer and target-therapies for clinical utility.
|Chaiswing, Luksana; St Clair, William H; St Clair, Daret K (2018) Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer. Antioxid Redox Signal 29:1237-1272|
|Zhong, Weixiong; Weiss, Heidi L; Jayswal, Rani D et al. (2018) Extracellular redox state shift: A novel approach to target prostate cancer invasion. Free Radic Biol Med 117:99-109|
|Chaiswing, Luksana; Weiss, Heidi L; Jayswal, Rani D et al. (2018) Profiles of Radioresistance Mechanisms in Prostate Cancer. Crit Rev Oncog 23:39-67|