Identification of serum and glucocorticoid-regulated kinase 1 as a regulator of signal transducer and activator of transcription 3 signaling.

Signal transducer and activator of transcription 3 (STAT3) plays key roles in cancer cell proliferation, invasion, and immunosuppression. In many human cancer cells, STAT3 is hyperactivated, which leads to tumor progression and drug resistance, and therefore STAT3 and its modulators are considered effective drug targets. However, the complex regulatory mechanisms of STAT3 have made it difficult to develop potent anticancer drugs that suppress its activity. Here, we report serum and glucocorticoid-regulated kinase 1 (SGK1) as a novel regulator of STAT3 signaling and an effective target for combination therapy with Janus kinase (JAK) inhibitors. We screened small molecules using a gain-of-function mutant of STAT3 resistant to JAK inhibition and found that an SGK1 inhibitor suppressed the constitutive activation of STAT3. Importantly, our results revealed that SGK1 also mediated the activation of wild-type STAT3. Further examination suggested that the tuberous sclerosis complex 2 and mammalian target of rapamycin signaling pathway were involved in STAT3 activation by SGK1. Finally, we demonstrated that SGK1 inhibition enhanced the inhibitory effect of a JAK inhibitor on STAT3 phosphorylation and cancer cell proliferation. Our findings provide new insights into the molecular mechanisms of STAT3 activation and suggest SGK1 as a potential target for STAT3-targeted combination cancer therapy.

Global Monitoring of Persistent Organic Pollutants (POPs) Using Seabird Preen Gland Oil.

Situated at high positions on marine food webs, seabirds accumulate high concentrations of persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs), and hexachlorocyclohexanes (HCHs). Our previous studies proposed the usefulness of seabirds preen gland oil as a nondestructive biomonitoring tool. The present study applied this approach to 154 adult birds of 24 species collected from 11 locations during 2005-2016 to demonstrate the utility of preen gland oil as a tool for global monitoring POPs, i.e., PCBs, DDTs, and HCHs. Concentrations of the POPs were higher in the Northern Hemisphere than in the Southern Hemisphere. In particular, ∑20PCBs and∑DDTs were highly concentrated in European shags (Phalacrocorax aristotelis) and Japanese cormorants (Phalacrocorax capillatus), explainable by a diet of benthic fishes. Higher concentrations of γ-HCH were detected in species from the polar regions, possibly reflecting the recent exposure and global distillation of ∑HCHs. We examined the relationship between age and POP concentrations in preen gland oil from 20 male European shags, aged 3-16 years old. Concentrations and compositions of POPs were not related to age. We also examined sex differences in the POP concentrations from 24 streaked shearwaters (Calonectris leucomelas) and did not detect a sex bias. These results underline the importance of the geographic concentration patterns and the dietary behavior as determinants species-specific POPs concentrations in preen gland oil.