Figure 6.

PAGE4 conformational switching gives rise to cell phenotypic oscillations which are suppressed by Androgen Deprivation treatments. (A) The PAGE4 phosphorylation circuit and its connection with androgen receptor (AR) activity. Wild-type PAGE4 is double-phosphorylated at two residues by HIPK1 kinase, and HIPK1-PAGE4 is hyper-phosphorylated by the CLK2 kinase. CLK2 is downregulated by AR, which in turn is inhibited by HIPK1-PAGE4 via the intermediates c-Jun. Androgen Deprivation treatment is introduced as an inhibitory signal on AR activity. (B) Temporal dynamics of the cellular level of WT PAGE4, HIPK1-PAGE4, CLK2-PAGE4 and CLK2. Without androgen-deprivation therapy (ADT), the oscillatory behavior exhibits a period of approximately one week (left area without shading). ADT (orange-shaded area) quenches oscillations within approximately two weeks. WT PAGE4, HIPK1-PAGE4, CLK2-PAGE4 and CLK2 are represented in dimensionless units. (C) Distribution of CLK2 intracellular levels in a simulated cohort of 10,000 prostate cancer (PCa) cells. In the absence of treatment, the distribution of CLK2 levels is broad (“Day 0” case). One week of treatment considerably shrinks the distribution (“Day 7” case). After two weeks of treatment, all cells have a similar level of CLK2 (“Day 14” case). (D) Temporal dynamics of CLK2-PAGE4 in four initially unsynchronized cells under intermittent ADT. The orange shading represents the periods of ADT. (E) Temporal dynamics of CLK2-PAGE4 in four initially unsynchronized cells under the BAT. The pink and orange shadings represent the periods of AR overexpression and ADT, respectively. Adopted from [41].