Oncotarget

Research Papers:

Function of phosphorylation of NF-kB p65 ser536 in prostate cancer oncogenesis

Li Zhang, Longjiang Shao, Chad J. Creighton, Yiqun Zhang, Li Xin, Michael Ittmann and Jianghua Wang _

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Oncotarget. 2015; 6:6281-6294. https://doi.org/10.18632/oncotarget.3366

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Abstract

Li Zhang1,2,*, Longjiang Shao2,*, Chad J. Creighton3,5, Yiqun Zhang3, Li Xin4, Michael Ittmann2 and Jianghua Wang2

1 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China

2 Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Deptartment of Veterans Affairs Medical Center, Houston, Texas, USA

3 Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, Texas, USA

4 Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

5 Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

* Theses authors contribute equally to this work

Correspondence to:

Jianghua Wang, email:

Keywords: Prostate cancer, TMPRSS2/ERG, NF-κB, AKT, CCL2

Received: December 16, 2014 Accepted: January 12, 2015 Published: January 31, 2015

Abstract

Majority of prostate cancer (PCa) patients carry TMPRSS2/ERG (T/E) fusion genes and there has been tremendous interest in understanding how the T/E fusion may promote progression of PCa. We showed that T/E fusion can activate NF-kB pathway by increasing phosphorylation of NF-kB p65 Ser536 (p536), but the function of p536 has never been studied in PCa. We report here that active p536 can significantly increase cell motility and transform PNT1a cells (an immortalized normal cell line), suggesting p536 plays a critical role in promoting PCa tumorigenesis. We have discovered a set of p536 regulated genes, among which we validated the regulation of CCL2 by p536. Based on all evidence, we favor that T/E fusion, NF-kB p536 and CCL2 form a signaling chain. Finally, PNT1a cells (not tumorigenic) can form tumors in SCID mice when overexpressing of either wild type or active p65 in the presence of activated AKT, demonstrating synergistic activities of NF-kB and AKT signals in promoting PCa tumorigenesis. These findings indicate that combination therapies targeting T/E fusion, NF-kB, CCL2 and/or AKT pathways may have efficacy in T/E fusion gene expressing PCa. If successful, such targeted therapy will benefit more than half of PCa patients who carry T/E fusions.


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