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

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

doi:10.18632/oncotarget.3366

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.

Highlights

In spite of recent progress, prostate cancer (PCa) is still the second leading cause of cancer death in US men
PNT1a cells 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
Our group and others have carried out extensive studies of the incidence of T/E fusions in PCa, the various expressed different isoforms expressed as well as their biologic functions in PCa during the past a few years[2, 9, 10, 36, 37]

Summary

Introduction

In spite of recent progress, prostate cancer (PCa) is still the second leading cause of cancer death in US men. PCa can be cured only if detected at an early localized stage using radical prostatectomy (RP) or radiation therapy. For recurrent or metastatic PCa, standard androgen ablation therapy usually results in initial regression of the disease. Almost all patients will fail this therapy in the long run and develop “androgenindependent” (AI) or “castrate-resistant” PCa (CRPC), the lethal phenotype of PCa. From the clinical perspective, PCa patients even with identical stage and grade of primary localized tumor may develop very variable clinical outcomes due to the underlying differences at the molecular level. Characterization of differences in molecular signature among different patients is critical for designing personalized medicine

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