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 that the resistance of PCa to radiation therapy is attributed to elevated expression of Hepatoma Up-Regulated Protein (HURP). In PCa cells, the induction of 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 the modulation of 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.
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.|Department of Pathology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Mohamed
M
Hassan
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Abdelouahid
A
El Khattouti
Department of Pathology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Ahmed
A
Ejaeidi
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Tangeng
T
Ma
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.|Department of Biology, Belhaven University, 1500 Peachtree Street Jackson, Mississippi, 39202.
William A
WA
Day
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.|Department of Biochemistry, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Ingrid
I
Espinoza
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.|Department of Radiation Oncology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Srinivasan
S
Vijayakumar
Cancer Institute, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.|Department of Pathology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.|Department of Radiation Oncology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216.
Christian R
CR
Gomez
D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
C465041:DLGAP5 protein, human; D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
APOPTOSIS; ASK1; HURP; JNK; PCa; γ-IRRADIATION