The Androgen Receptor Bridges Stem Cell-Associated Signaling Nodes in Prostate Stem Cells

Figure 1

Regulation of interconnected stem cell signaling nodes by the AR. Activation of the AR negatively regulates the core pluripotency transcription factors (Nanog, Sox2, and Oct4) as well as signaling cascades that reinforce a robust stem cell state. The AR (1) acts as a transcriptional repressor at the Nanog and Sox2 promoters; (2) inhibits PI3K/Akt signaling through induction of PHLPP, which dephosphorylates Akt to facilitate ERK pathway activation leading to Nanog gene repression, as well as GSK3-mediated c-myc and β-catenin repression; and (3) blocks STAT3-mediated transcription of stem cell-associated genes by inhibiting IL-6. Suppression of the AR by factors in the stem cell niche, such as CCL5, relieves this inhibition to favor self-renewal and pluripotency over differentiation. AR, androgen receptor; β-CAT, β-catenin; CCL5, chemokine ligand 5; IL-6, interleukin-6; JAK, Janus kinase; PHLPP, PH domain and leucine rich protein phosphatase; RTK, receptor tyrosine kinase.