Timothy W Stark1, Patrick J Hensley1,2, Amanda Spear3, Hong Pu1, Stephen S Strup1, Natasha Kyprianou1,4. 1. Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky. 2. Department of Pathology, University of Kentucky College of Medicine, Lexington, Kentucky. 3. Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky. 4. Department of Molecular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky.
Abstract
INTRODUCTION: Epithelial-mesenchymal-transition (EMT) has been previously identified as a contributor to prostate cancer progression to metastasis and therapeutic resistance to antiandrogens and radiotherapy. In this study we conducted a retrospective analysis to investigate the significance of radiation-induced EMT and consequential changes to the tumor microenvironment in biochemical recurrence and response to radiotherapy in prostate cancer patients. METHODS: Expression profiling and localization for EMT effectors, E-Cadherin, N-Cadherin, β-catenin and Vimentin was assessed in human prostate tumor specimens pre- and post-radiotherapy and correlated with biochemical recurrence. In addition, immunoreactivity of the DNA repair enzyme, polymerase (PARP-1) and the cytoskeletal-remodeling regulator, cofilin was evaluated in prostate tumor specimens pre- and post-radiotherapy and correlated with pre-treatment prostate-specific antigen levels (PSA). RESULTS: Our findings identified that characteristic changes associated with the EMT phenotype and its reversal to mesenchymal-epithelial-transition (MET) within the tumor microenvironment correlate with biochemical recurrence and resistance to radiotherapy among prostate cancer patients. Moreover, elevated PARP-1 expression among the tumor cells undergoing EMT implicates that DNA repair mechanisms may potentially reverse the cytotoxic effects of radiotherapy-induced DNA breaks. CONCLUSIONS: Our results suggest that EMT programming effectors, integrated with the actin cytoskeleton regulator cofilin and mesenchymal PARP-1 expression profile provide a signature of potential predictive significance of therapeutic response to radiotherapy in a subset of prostate cancer patients.
INTRODUCTION: Epithelial-mesenchymal-transition (EMT) has been previously identified as a contributor to prostate cancer progression to metastasis and therapeutic resistance to antiandrogens and radiotherapy. In this study we conducted a retrospective analysis to investigate the significance of radiation-induced EMT and consequential changes to the tumor microenvironment in biochemical recurrence and response to radiotherapy in prostate cancerpatients. METHODS: Expression profiling and localization for EMT effectors, E-Cadherin, N-Cadherin, β-catenin and Vimentin was assessed in humanprostate tumor specimens pre- and post-radiotherapy and correlated with biochemical recurrence. In addition, immunoreactivity of the DNA repair enzyme, polymerase (PARP-1) and the cytoskeletal-remodeling regulator, cofilin was evaluated in prostate tumor specimens pre- and post-radiotherapy and correlated with pre-treatment prostate-specific antigen levels (PSA). RESULTS: Our findings identified that characteristic changes associated with the EMT phenotype and its reversal to mesenchymal-epithelial-transition (MET) within the tumor microenvironment correlate with biochemical recurrence and resistance to radiotherapy among prostate cancerpatients. Moreover, elevated PARP-1 expression among the tumor cells undergoing EMT implicates that DNA repair mechanisms may potentially reverse the cytotoxic effects of radiotherapy-induced DNA breaks. CONCLUSIONS: Our results suggest that EMT programming effectors, integrated with the actin cytoskeleton regulator cofilin and mesenchymal PARP-1 expression profile provide a signature of potential predictive significance of therapeutic response to radiotherapy in a subset of prostate cancerpatients.
Authors: Shan-Shan Yang; De-Yang Yu; Yu-Ting Du; Le Wang; Lina Gu; Yun-Yan Zhang; Min Xiao Journal: Cancer Cell Int Date: 2020-07-28 Impact factor: 5.722
Authors: Patrick J Hensley; Natasha Kyprianou; Matthew S Purdom; Daheng He; Vincent DiCarlo; Chi Wang; Andrew C James Journal: Urol Oncol Date: 2019-07-17 Impact factor: 2.954
Authors: Caroline N Barquilha; Nilton J Santos; Caio C D Monção; Isabela C Barbosa; Flávio O Lima; Luis A Justulin; Nelma Pértega-Gomes; Sérgio L Felisbino Journal: Oxid Med Cell Longev Date: 2020-01-20 Impact factor: 6.543