Elevated Expression of Hepatoma Up-Regulated Protein Inhibits γ- Irradiation- Induced Apoptosis of Prostate Cancer Cells.

Despite progression in diagnosis and treatment, prostate cancer (PCa) still represents the main cause of cancer-related mortality and morbidity in men. Although radiation therapy offers clinical benefit over other therapeutic modalities, the success of this therapeutic modality is commonly hampered by the resistance of advanced tumors.

So far, the mechanisms governing tumor resistance to radiotherapy are not discussed in detail. Here, we demonstrate for the first time PCa radio-resistance as a consequence of elevated expression of Hepatoma Up-Regulated Protein (HURP). In PCa cells, HURP expression suppresses γ- irradiation- induced apoptosis. γ- irradiation-induced apoptosis of PCa cells is associated with expression of E2F1, p53, p21 proteins together with the phosphorylation of apoptosis signal-regulating kinase1 (ASK1), c-jun-N-terminal kinase (JNK) and Ataxia-telangiectasia mutated (ATM) and histone family member X (H2AX). Whereas, the induction of HURP expression is able to suppress γ- irradiation- induced effects on E2F1, p53, p21, ATM, ASK1, JNK and ATM, and H2AX. Also, inhibition of γ- irradiation- induced- cytochrome c release, cleavage of caspase-9, caspase-3, PARP, and reactive oxygen species (ROS) were noted in PCa cells induced for HURP expression. The observed radio-resistance of PCa is thought to be the consequence of HURP-mediated destabilization of p53 and ATM proteins that are essential for γ-irradiation-induced apoptosis. Thus, based on our findings, PCa resistance to radiation therapy results from the deregulation of ASK1/ JNK; ATM/ H2AX; ATM/p53 and checkpoint kinase 2 (Chk2)/ E2F-1 in response to the elevated expression of HURP. This article is protected by copyright. All rights reserved.

Journal of cellular biochemistry. 2015 Oct 27 [Epub ahead of print]

Mohamed Hassan, Abdelouahid El Khattouti, Ahmed Ejaeidi, Tangeng Ma, William A Day, Ingrid Espinoza, Srinivasan Vijayakumar, Christian R Gomez

Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Department of Pathology, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Department of Biochemistry, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216. , Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, MS 39216.

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