FIGURE 1. Model for CaMKK2 functions in prostate cancer biology.

In macrophages, PAMPs and DAMPs bind PRRs and trigger downstream signals, which synergize with integrin-signaling generated at the macrophage-cancer interface. In macrophages: CaMKK2 regulates crosstalk between PPR- and integrin-signals required for maximal activation of PYK2. In turn, PYK2 controls cytoskeleton organization and cytokine gene expression. CaMKI and AMPK are downstream targets of CaMKK2, which regulates metabolic response and gene expression in response to PRR/integrin stimulation. Cytokines released by activated macrophages induce TAB2 phosphorylation and remove the co-repressor N-COR/HDAC from the androgen receptor (AR)-promoter, which in turn converts the new androgen receptor antagonist used in PC from their intended function as inhibitors of androgen receptor-induced gene expression to activators. In prostate cancer cells: androgens bind and activate AR, which moves to the nucleus and enhances Camkk2 gene expression. CaMKK2 participates in a positive feedback loop by stimulating AR-dependent transcriptional activity. The CaMKK2-AMPK axis controls glucose metabolism, growth and cell migration. In this model, CaMKK2 is an important component of AR signaling, and a pivotal player of networks controlling macrophage activation and prostate cancer biology. Dotted arrows indicate functional interactions not yet supported by experimental evidence. Abbreviations: PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; PRR, pattern recognition receptors; AR, androgen receptor; HDAC, histone deacetylase.