Proteasome Inhibition in Osteosarcoma Therapy

Introduction Osteosarcoma (OS) is a primary bone cancer that affects children and young adults. OS has a poor prognosis due to propensity for lung metastasis, resistance to radiation and inconsistent response to chemotherapy. We have previously determined that OS aggressiveness and resistance to apoptosis is associated with the increased NF-κB activity. In addition, we and others have shown that the loss of function of a major osteoblastic differentiation factor, Runx2, contributes to the aggressive and undifferentiated phenotype in OS and that gain of Runx2 function inhibits proliferation and induces apoptosis in OS cell lines. We also demonstrated that Runx2 transcriptionally activates a major pro-apoptotic gene, Bax, thereby sensitizing cells to apoptosis. Based on the above, we assumed that inhibition of NF-κB and induction of Runx2 may suppress OS growth and sensitize OS to apoptosis. NF-κB and Runx2 are inversely regulated by the proteasome and proteasome inhibitors have been shown to suppress NF-κB and, on the other hand, induce Runx2 function. We, therefore, hypothesized that the proteasome inhibitor, bortezomib (Bzm), via suppression of NF-κB and induction of Runx2, may inhibit tumor growth and induce apoptosis in OS.