Angiogenesis is essential for promoting growth and
metastasis of solid
tumors by ensuring blood supply to the
tumor mass. Targeting angiogenesis is therefore an attractive approach to therapeutic intervention of
cancer.
Tumor angiogenesis is a process that is controlled by a complex network of molecular components including sensors, signaling transducers, and effectors, leading to cellular responses under hypoxic conditions. Positioned at the center of this network are the
hypoxia-inducible factors (HIFs). HIF-1 is a major
transcription factor that consists of two subunits, HIF-1α and HIF-1β. It mediates transcription of a spectrum of gene targets whose products are essential for mounting hypoxic responses. HIF-1α
protein level is very low in the normoxic condition but is rapidly elevated under
hypoxia. This dramatic change in the cellular HIF-1α level is primarily regulated through the proteosome-mediated degradation process. In the past few years, scientific progress has clearly demonstrated that HIF-1α phosphorylation is mediated by several families of
protein kinases including GSK3β and ERKs both of which play crucial roles in the regulation of HIF-1α stability. Recent research progress has identified that Polo-like
kinase 3 (Plk3) phosphorylates HIF-1α at two previously unidentified
serine residues and that the Plk3-mediated phosphorylation of these residues results in destabilization of HIF-1α. Plk3 has also recently been found to phosphorylate and stabilize
PTEN phosphatase, a known regulator of HIF-1α and
tumor angiogenesis. Given the success of targeting
protein kinases and
tumor angiogenesis in anti-
cancer therapies, Plk3 could be a potential molecular target for the development of novel and effective therapeutic agents for
cancer treatment.