Antineoplastic Therapy in Colorectal Cancer through Proteasome Inhibition

Abstract

Upregulation of nuclear factor (NF)-κB is found in many forms of cancer. Activation of NF-κB in cancer cells by chemotherapy or radiation can blunt the ability of this therapy to induce cell death. Proteasome inhibitors stimulate apoptosis in part via prevention of NF-κB activation. We sought to determine whether constitutive NF-κB activity is present in human colon cancer. In addition we studied whether alterations of NF-κB activity with a proteasome inhibitor would prevent colon cancer cell growth and induce apoptosis. We demonstrated constitutive transcriptional activation of NF-κB in SW48 and SW116 colon cancer cells by luciferase and electromobility shift assays. This was confirmed by p65 immunostaining. This activity was further induced in the presence of chemotherapy. In colon cancer specimens constitutive activation of NF-κB was observed in the majority of tumors. Treatment with the proteasome inhibitor (MG-132) inhibited growth and also stimulated apoptosis of colon cancer cells. We conclude that inhibition of NF-κB activation may be a logical therapy for certain cancers. This can be done via specific approaches on molecules necessary for keeping NF-κB inactivated in the cytoplasm. Other potentially useful ways to promote apoptosis in cancer cells include the utilization of proteasome inhibitors. Such inhibitors are currently being evaluated in clinical trials.