PDCD10 promotes the aggressive behaviors of pituitary adenomas by up-regulating CXCR2 and activating downstream AKT/ERK signaling.

As the second most common primary intracranial neoplasms, about 40% of pituitary adenomas (PAs) exhibit aggressive behaviors and resulting in poor patient prognosis. The molecular mechanisms underlying the aggressive behaviors of PAs are not yet fully understood. Biochemical studies have reported that programmed cell death 10 (PDCD10) is a component of the striatin-interacting phosphatase and kinase (STRIPAK) complex and plays a dual role in cancers in a tissue- or disease-specific manner. In the present study, we report for the first time that the role of PDCD10 in PAs. Cell proliferation, migration and invasion were either enhanced by overexpressing or inhibited by silencing PDCD10 in PA cells. Moreover, PDCD10 significantly promoted epithelial-mesenchymal transition (EMT) of pituitary adenoma cells. Mechanistically, we showed that the expression of CXCR2, together with phosphorylation levels of AKT and ERK1/2 were regulated by PDCD10. Activation of CXCR2 inversed inactivation of AKT/ERK signal pathways and the tumor-suppressive effects induced by PDCD10 silencing. Finally, the pro-oncogenic effect of PDCD10 was confirmed by in vivo tumor grafting. Taken together, we demonstrate for the first time that PDCD10 can induce aggressive behaviors of PAs by promoting cellular proliferation, migration, invasion and EMT through CXCR2-AKT/ERK signaling axis.

ZIP9 but not the androgen receptor mediates testosterone-induced migratory activity of metastatic prostate cancer cells.

LNCaP cells are derived from a metastatic lesion of human prostate adenocarcinoma. They express the classical androgen receptor (AR) and ZIP9, a Zn2+ transporter that also binds testosterone and mediates signaling by interacting with G-proteins. Our results show that LNCaP cells respond to testosterone by mobilizing their migratory machinery. Their exposure to testosterone triggers the formation of lamellipodia, reorganization of the actin cytoskeleton, phosphorylation of focal adhesion kinase (FAK) at Tyr925 and of paxillin at Tyr118, expression of matrix metalloproteinase 2 (MMP-2), and cell migration. Silencing ZIP9 expression by means of siRNA does not affect the responsiveness of the classical AR to testosterone; however, it prevents all of the testosterone effects described above: formation of lamellipodia cannot be induced, stimulation of FAK or paxillin phosphorylation or MMP-2 expression is prevented, and cell migration does not take place in the absence of ZIP9. The data presented show that testosterone/ZIP9 interactions might have not only physiological but also pathophysiological relevance. The fact that the migratory machinery of a metastatic prostate cancer cell line is activated exclusively through testosterone/ZIP9 and not through testosterone/AR interactions suggests that targeting specific inhibition of testosterone/ZIP9-mediated events might help in developing new therapeutic strategies against androgen-induced progression of prostate cancer.

A Rationale for Targeting Extracellular Regulated Kinases ERK1 and ERK2 in Glioblastoma.

Glioblastoma (GBM) is the most common malignant primary brain tumor. It still carries a grim prognosis and new therapies are needed. This review summarizes the current status of mechanistic insights into the function of extracellular regulated kinase (ERK) and its potential as a therapeutic target for patients with GBM. Currently, some promising ERK inhibitors are in clinical trials in tumor entities other than GBM. Here, we provide a comprehensive overview on the functions of ERK1/2 in GBM and a rationale for treatment of GBM with ERK inhibitors.