Abstract
Early stage prostate cancers are dependent on androgens for their growth and survival and androgen withdrawal causes them to regress. Progressive prostate cancers eventually acquire androgen independence rendering anti-androgen therapy ineffective. However, the factors leading to this have not been adequately addressed. This study shows that AIRE finds differential expression in androgen-dependent and -independent prostate cancer cells. AIRE expression is more in androgen-independent cells due to its regulation by transcription factor Elk-1. These enhanced levels of AIRE modulate the prostate tumor microenvironment by transcriptionally activating a malignancy gene IL-6 in androgen-independent cells. Additionally, AIRE prevents the cancer cells from anticancer drug-induced death and enhances their invasiveness. Moreover, AIRE by modulating the cytokine milieu skews the tumor-associated macrophage polarization towards M2 phenotype with increased CD206 and CD163 expression. Subcutaneous mouse model of prostate cancer revealed AIRE+/+ mice forming a palpable tumor and presents lymphadenopathy however, only a small benign tumor is observed in AIRE−/− mice and lymph nodes appear normal in size. In conclusion, our findings suggest AIRE as a probable factor in promoting prostate cancer progression.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous neoplasm and ranks second in cancerrelated deaths among men
To dissect the mechanism behind androgendependent and -independent prostate cancer we used two cell lines which are androgen sensitive, i.e. LNCaP and VCaP and two cell lines which are insensitive to androgens, i.e. PC3 and DU145 and all of them are epithelial in origin
We further analyzed IL-6 expression levels by enzyme-linked immunosorbent assay (ELISA) in supernatant of cells with autoimmune regulator (AIRE) overexpression and knockdown and we clearly observed a significant increase in IL-6 secretion by AIRE which gets decreased in RNAimediated knockdown of AIRE (Fig. 1d, e)
Summary
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous neoplasm and ranks second in cancerrelated deaths among men. Despite recent advancements in the treatment of the disease, patients with the malignant disease have a poor survival rate[1]. PCa is initially androgen-dependent for its progression and androgen ablation remains to be the mainstay of therapy for patients with advanced cancers. This hormone withdrawal is palliative in more than 50% of the patients yet the effects are transient. AR by binding to biologically active androgens transcriptionally regulates expression of its target genes. Immune gene encoding autoimmune regulator (AIRE) protein which confers autoimmune protection has been found to be regulated by androgen/AR complex in androgen-dependent LNCaP cells which endogenously express AR.
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