Glioblastoma multiforme, a highly aggressive
tumor of the central nervous system, has a dismal prognosis that is due in part to its resistance to radio- and
chemotherapy. The
protein kinase C (PKC) family of
serine threonine kinases has been implicated in the formation and proliferation of
glioblastoma multiforme. Members of the
protein kinase D (PKD) family, which consists of PKD1, -2 and, -3, are prominent downstream targets of
PKCs and could play a major role in
glioblastoma growth. PKD2 was highly expressed in both low-grade and high-grade human
gliomas. The number of PKD2-positive
tumor cells increased with
glioma grading (P < .001). PKD2 was also expressed in CD133-positive
glioblastoma stem cells and various
glioblastoma cell lines in which the
kinase was found to be constitutively active. Inhibition of PKDs by pharmacological inhibitors resulted in substantial inhibition of
glioblastoma proliferation. Furthermore, specific depletion of PKD2 by
siRNA resulted in a marked inhibition of anchorage-dependent and -independent proliferation and an accumulation of
glioblastoma cells in G0/G1, accompanied by a down-regulation of
cyclin D1 expression. In addition, PKD2-depleted
glioblastoma cells exhibited substantially reduced
tumor formation in vivo on chicken chorioallantoic membranes. These findings identify PKD2 as a novel mediator of
glioblastoma cell growth in vitro and in vivo and thereby as a potential therapeutic target for this devastating disease.