The PIM1 kinase promotes prostate cancer cell migration and adhesion via multiple signalling pathways.

The ability of cells to migrate and form metastases is one of the fatal hallmarks of cancer that can be conquered only with better understanding of the molecules and regulatory mechanisms involved. The oncogenic PIM kinases have been shown to support cancer cell survival and motility, but the PIM-regulated pathways stimulating cell migration and invasion are less well characterized than those affecting cell survival. Here we have identified the glycogen synthase kinase 3ß (GSK3B) and the forkhead box P3 (FOXP3) transcription factor as direct PIM targets, whose tumour-suppressive effects in prostate cancer cells are inhibited by PIM-induced phosphorylation, resulting in increased cell migration. Targeting GSK3B is also essential for the observed PIM-enhanced expression of the prostaglandin-endoperoxide synthase 2 (PTGS2), which is an important regulator of both cell migration and adhesion. Accordingly, selective inhibition of PIM activity not only reduces cell migration, but also affects integrin-mediated cell adhesion. Taken together, these data provide novel mechanistic insights on how and why patients with metastatic prostate cancer may benefit from therapies targeting PIM kinases, and how such approaches may also be applicable to inflammatory conditions.

Self-reported pain interference and symptoms of anxiety and depression in community-dwelling older adults: can a temporal relationship be determined?

Pain and symptoms of depression and anxiety have been observed to co-exist in the community-dwelling elderly. While depression and pain have been suggested to be predictive of one another temporally, the longitudinal associations between anxiety and pain remain undefined. The aim of this study was to investigate the reciprocal longitudinal associations of self-reported pain interference and affective symptoms, as measured by the Hospital Anxiety and Depression Scale, in community-dwelling older adults and report the potentially modifying effect of co-morbid anxiety or depression on these relationships. The study population were adults aged over 50-years, recruited previously to the North Staffordshire Osteoarthritis project (NorStOP), who had returned a health survey at both baseline and 3-year follow-up (n=4234). Logistic regression was used to evaluate the pain-affect associations, with associations expressed as odds ratios with 95% confidence intervals (CI). Probable depression (odds ratio=2.42; 95% CI 1.24, 4.69) and anxiety (2.30; 1.67, 3.17) at baseline predicted new-onset pain interference at 3-year follow-up. Conversely, pain interference at baseline was a risk factor for developing possible or probable depression (2.47; 1.96, 3.11) and anxiety (2.02; 1.60, 2.55) at 3-year follow-up. Adjusting for age, gender and co-morbid anxiety or depression slightly reduced the strength of the relationships, though most remained statistically significant. In conclusion, we have found evidence for both pain-depression and pain-anxiety relationships longitudinally, and in a reciprocal manner. Such findings have important implications for the future management of primary care patients presenting with symptoms of pain, anxiety or depression.