ABSTRACT
It is well-established that intermediate challenge is optimally motivating. We tested whether this can be quantified into an inverted-U relationship between motivation and success frequency. Participants played a game in which they navigated a scene to catch targets. In Experiment 1 (N = 101), play duration was free and the motivating value of success frequency was measured from the probability that a player would continue at that frequency. In Experiment 2 (N = 70), play duration was fixed, and motivation was measured using repeated self-reports. In Experiment 1, the probability to continue increased linearly with the success frequency whereas play duration did show the inverted-U relationship with success frequency. In Experiment 2, self-reported motivation showed the inverted-U relationship with success frequency. Together, this shows that motivation depends on success frequency. In addition, we provide tentative evidence that the concept of intermediate challenge being most motivating can be quantified into an inverted-U relationship between motivation and success frequency.
ABSTRACT
Cancer cells with stem or progenitor properties play a pivotal role in the initiation, recurrence and metastatic potential of solid tumors, including those of the human prostate. Cancer stem cells are generally more resistant to conventional therapies thus requiring the characterization of key pathways involved in the formation and/or maintenance of this malignant cellular subpopulation. To this end, we identified Glycogen Synthase Kinase-3ß (GSK-3ß) as a crucial kinase for the maintenance of prostate cancer stem/progenitor-like cells and pharmacologic inhibition of GSK-3ß dramatically decreased the size of this cellular subpopulation. This was paralleled by impaired clonogenicity, decreased migratory potential and dramatic morphological changes. In line with our in vitro observations, treatment with a GSK-3ß inhibitor leads to a complete loss of tumorigenicity and a decrease in metastatic potential in preclinical in vivo models. These observed anti-tumor effects appear to be largely Wnt-independent as simultaneous Wnt inhibition does not reverse the observed antitumor effects of GSK-3ß blockage. We found that GSK-3ß activity is linked to cytoskeletal protein F-actin and inhibition of GSK-3ß leads to disturbance of F-actin polymerization. This may underlie the dramatic effects of GSK-3ß inhibition on prostate cancer migration. Furthermore, GSK-3ß inhibition led to strongly decreased expression of several integrin types including the cancer stem cell-associated α2ß1 integrin. Taken together, our mechanistic observations highlight the importance of GSK-3ß activity in prostate cancer stemness and may facilitate the development of novel therapy for advanced prostate cancer.
