Defining the Role of PIM1 in Tumor Angiogenesis

Abstract

PIM1 is a serine/threonine kinase that is upregulated in cancer. PIM1 is constitutively active upon translation, so protein levels equate to activity. Researchers have connected PIM1 signaling with pro-survival and pro-proliferative roles; however, little is known about how PIM1 is upregulated in cancer and the extent of its participation in other hallmarks of cancer. Here, we identified that PIM1 is upregulated in response to hypoxia in solid tumors via disruption of its proteasomal regulation. Here, I establish that heightened PIM1 expression promotes tumor angiogenesis via direct phosphorylation of HIF-1. Using orthotopic and xenograft models of prostate and colon cancer, we demonstrated that co-inhibition of PIM and VEGF produces synergistic anti-tumor effects. Finally, we have linked PIM1 expression to increased invasion capacity in macrophage and bone-marrow derived myeloid cells, both of which support tumorigenesis. Future studies will explore how hypoxia disrupts the proteasomal regulation of PIM1 and investigate signaling between PIM1 and macrophages and whether PIM inhibitors could be used to alter immune response. The long-term goal of this study is to expand our understand of PIM1 signaling in order to develop the best therapeutic approach to maximize the efficacy of PIM inhibitors in the clinic.