Antinuclear autoantibodies in prostate cancer: Immunity to LEDGF/p75, a survival protein highly expressed in prostate tumors and cleaved during apoptosis

Abstract

The high expression of LEDGF/p75 in prostate tumors and BPH could be induced by inflammation and oxidative stress. LEDGF/p75 cleavage fragments generated during prostate tumor cell death might trigger autoantibodies under inflammatory conditions in certain patients.

Integrase, LEDGF/p75 and HIV replication

“…In −/− mouse embryonic fibroblasts (MEFs) fewer genes were up-or down-regulated (< 200) and, again, a particular transcriptional network was not identified [101]. Studies focused on other biological questions have implicated p75 in modulating apoptosis and other cellular responses to stress and have suggested a role as an auto-antigen in certain disease states [66][67][68][70][71][72]84,107]. However, p75 depletion does not disproportionately alter stress-responsive gene transcription, nor does HIV appear to preferentially target such genes [85,101,110].…”

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

“…These autoantibodies have been detected in several human cancers, and significant advances have been made in the identification of their target antigens, particularly in lung cancer (28,30), colorectal cancer (36), breast cancer (29), prostate cancer (27,37), leukemia (26), non-Hodgkin lymphoma (24), hepatocellular carcinoma (25,32,34), ovarian cancer (31), pancreatic cancer (33,38), and paraneoplastic neurological syndromes (35). Although the mechanisms leading to autoantibody production in cancer patients are not clearly understood, emerging evidence indicates that most TAAs are cellular proteins whose aberrant regulation or function could be linked to malignancy (3).…”

“…Although the mechanisms leading to autoantibody production in cancer patients are not clearly understood, emerging evidence indicates that most TAAs are cellular proteins whose aberrant regulation or function could be linked to malignancy (3). For instance, TAAs include known oncoproteins such as HER-2/ Neu and c-MYC (46 -49); tumor suppressor proteins such as p53 (50); survival proteins such as survivin and lens epithelium-derived growth factor (LEDGF/p75) (27,51); cell cycle regulatory proteins such as cyclin B1 (52); mitosis-associated proteins such as centromere protein F (CENP-F) (25,53,54); chromatin-associated proteins such as topoisomerases (29,55); mRNA-binding proteins such as p62, IMP1, and Koc (56,57); and differentiation and cancer testis antigens such as NY-ESO-1 (58).…”

“…This resistance is associated with overexpression of survival and antioxidant proteins in tumors, which could lead to loss of immune tolerance and provoke autoantibody responses. We reported recently that LEDGF/p75 (also known as the DFS70 autoantigen), a transcription co-activator that is upregulated by increased oxidative stress, is overexpressed in prostate tumors and targeted by autoantibodies in ϳ20% of patients with prostate cancer compared with a frequency of 5% in age-and gender-matched individuals with no history of prostate cancer (27). Although originally identified as a transcription co-activator and a growth and survival factor in lens epithelial cells (82,83), LEDGF/p75 is now known to be ubiquitously expressed in tumor cells and is emerging as a key regulator of the cellular response to stress (84,85).…”

An experimental strategy for quantitative analysis of the humoral immune response to prostate cancer antigens using natural protein microarrays

“…For example, antibodies have been detected in serum or plasma of prostate cancer patients against proteins such as alpha-methyl-acyl-CoA racemase (AMACR) [15], enhancer of zeste homolog 2 (EZH2) [16], PSA [17], HER-2/neu [17], secretory granules of the prostate [18], and lens epithelium-derived growth factor p75 (LEDGF/p75) [19]. The high prevalence of a tumor-associated immune response in patients with prostate cancers was shown in a study of a panel of six tumor-associated antigens [20] with a positive response in cancers at 92.5% vs. 14.8% in normals, as well as with microarrays of phage-displayed polypeptides at a specificity of 88.2% and 81.6% sensitivity [7].…”