Phosphorylated Pak1 level in the cytoplasm correlates with shorter survival time in patients with glioblastoma

Purpose: Glioblastoma is the most common primary malignant tumor in the brain. It aggressively invades the surrounding parenchyma, often allowing the tumor to progress after surgery. Accumulating evidence has shown that phosphorylated p2l -activated kinase 1 (Pakl), a mediator of small guanosine triphosphatases, plays a role in the proliferation, survival, and invasiveness of cancer cells. Thus, we examined patterns of Pakl expression in glioblastoma and sought to determine whether the level of phosphorylated Pakl in glioblastoma cells is associated with patient survival time. Experimental Design: We carried out immunohistochemical staining for phosphorylated Pakl in tumor specimens from 136 patients with glioblastoma; the tumors were classified according to Pakl protein levels in the cytoplasm and nucleus. We compared the patients' overall survival times using Kaplan-Meier analysis and estimated the effects of levels of cytoplasmic or nuclear phosphorylated Pakl. We then down-regulated Pakl by using small interfering RNA to knock down Pakl in two glioblastoma cell lines to determine whether Pakl contributed to cell viability and invasion. Results: Median overall survival was significantly shorter in patients with tumors showing a moderate or high level of cytoplasmic phosphorylated Pakl than in patients with tumors showing no cytoplasmic phosphorylated Pakl. The level of nuclear phosphorylated Pakl was not related to survival time. Knockdown of Pakl suppressed the invasion, but not the viability, of U87-MG and U373-MG cells. Conclusions: The presence of phosphorylated Pakl in the cytoplasm of glioblastoma cells is associated with shorter survival, and Pakl plays a role in the invasiveness of glioblastoma. These data suggest that Pakl might be a potential target for the management of glioblastoma.