• The Role of Osteopontin in Prostate Cancer Progression

      Robertson, Brian W.; Chellaiah, Meenakshi A. (2009)
      Our research investigates the relationship between the local environment of bone and how it influences the proliferation and metastasis of prostate cancer. Our focus centers on the bone extracellular matrix protein Osteopontin (OPN), which has previously been demonstrated to be an autocrine motility factor secreted by both osteoclasts and osteoblasts. In order to investigate the role of OPN in prostate cancer progression, we primarily employ PC3 prostate cancer cells derived from bony metastasis, but also look at the role of OPN in DU145 prostate cancer cells, and the lowly tumorigenic prostate cancer cell line LNCaP. OPN has been shown to activate Akt, and here we thoroughly define the OPN induced Akt cell survival pathway. Investigating the downstream players of activated Akt, we show that OPN induces an Akt-mediated increase in β-Catenin. Here we reveal a novel role for OPN, in inducing increased transcription of the TCF/LEF family of genes, of which β-catenin enhances as a co-factor after nuclear import. In an effort to more fully understand the role of OPN in prostate cancer progression, we investigated its role in MAPK signaling. Over-expression of OPN in PC3 cells resulted in the induced activation of the Erk1/2 pathway. Recently the field has determined that the metastatic potential of tumors or cancer cell lines can be measured through the scope of an Epithelial to Mesenchymal Transition(EMT). An EMT is typically characterized by a loss of E-Cadherin, an increase in N-Cadherin, and an increase in Vimentin. In order to more fully characterize the role of OPN in prostate cancer cell motility and metastasis, we probed the levels of EMT associated proteins. Surprisingly we found that OPN induces the opposite of an MET, a Mesenchymal to Epithelial Transition (MET), which is characterized by a more epithelial phenotype. Our results demonstrate that OPN can play many roles in prostate cancer progression, OPN increases survival of prostate cancer cells, OPN increases the expression of proteins important for cancer progression, and OPN helps to provide a means in which cancerous cells can aggregate and colonize a site of distant metastasis.