ABSTRACT
Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population.
Subject(s)
Cytidine Deaminase/metabolism , Homologous Recombination/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Active Transport, Cell Nucleus/drug effects , Active Transport, Cell Nucleus/radiation effects , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/enzymology , B-Lymphocytes/pathology , B-Lymphocytes/radiation effects , Cell Death/drug effects , Cell Death/radiation effects , Cell Line, Transformed , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cytidine Deaminase/genetics , DNA Breaks, Double-Stranded/drug effects , DNA Breaks, Double-Stranded/radiation effects , DNA Repair/drug effects , DNA Repair/radiation effects , Gene Expression Regulation, Leukemic/drug effects , Gene Expression Regulation, Leukemic/radiation effects , Histones/metabolism , Homologous Recombination/drug effects , Homologous Recombination/radiation effects , Humans , Mice , Rad51 Recombinase/metabolism , Radiation, IonizingABSTRACT
Advanced prostate tumors, which are androgen dependent, are often initially treated in the clinic with hormone ablation therapy, either through surgical castration or administration of small-molecule antiandrogens. Most tumors respond favorably to these treatments, exhibiting regression of the tumor, amelioration of symptoms, and a decrease of prostate-specific antigen in patient sera. However, with time, the majority of tumors recur in a more aggressive, castration-resistant (CR) phenotype. Currently, no effective treatment exists for this stage of the cancer, and patients ultimately succumb to metastatic disease. The androgen receptor (AR), which is a member of the nuclear hormone receptor superfamily of proteins, is the transcription factor that is responsible for mediating the effects of androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of prostate cancer. Despite CR tumor cells being able to continue to grow after hormonal therapy in which testosterone and dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR. The AR can become transactivated in this low-androgen environment through a number of different mechanisms, including amplification and mutation of the receptor, cross talk with other signaling pathways, and altered regulation by coregulatory proteins. This review will summarize the most current data regarding non-ligand-mediated activation of the AR in prostate cancer cells. Developing work in this field aims to more clearly elucidate the signals that drive AR activity independently of androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate carcinoma.
Subject(s)
Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Signal Transduction , Animals , Cytokines/metabolism , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Male , Mutation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/physiopathology , Protein Kinases/metabolism , Receptors, Androgen/genetics , Signal Transduction/geneticsABSTRACT
The biological action of androgenic male sex steroid hormones in prostate tissue is mediated by the androgen receptor, a nuclear transcription factor. The transcriptional program of androgenic signaling in the prostate consists of thousands of gene targets whose products play a role in almost all cellular functions, including cellular proliferation, survival, lipid metabolism, and differentiation. This review will provide a summary of the most recent data regarding androgen-regulated target genes and modulation of androgen receptor activity, especially with regard to androgen-dependent and castration-recurrent prostate cancer.
