Proteasome Inhibition Activates Epidermal Growth Factor Receptor (EGFR) and EGFR-Independent Mitogenic Kinase Signaling Pathways in Pancreatic Cancer Cells

Abstract

Purpose: In the current study, we investigate the activation of antiapoptotic signaling pathways in response to proteasome inhibitor treatment in pancreatic cancer and evaluate the use of concomitant inhibition of these pathways to augment proteasome inhibitor treatment responses. Experimental Design: Pancreatic cancer cell lines and mouse flank xenografts were treated with proteasome inhibitor alone or in combination with chemotherapeutic compounds (gemcitabine, erlotinib, and bevacizumab), induction of apoptosis and effects on tumor growth were assessed. The effect of bortezomib (a first-generation proteasome inhibitor) and NPI-0052 (a second-generation proteasome inhibitor) treatment on key pancreatic mitogenic and antiapoptotic pathways [epidermal growth factor receptor, extracellular signal-regulated kinase, and phosphoinositide-3-kinase (PI3K)/AKT] was determined and the ability of inhibitors of these pathways to enhance the effects of proteasome inhibition was assessed in vitro and in vivo.

Proteasome inhibitor MG-132 induces C6 glioma cell apoptosis via oxidative stress

“…However, activation of the PI3K/AKT pathways impaired the response of tumor cells to proteasome inhibitor treatment, and inhibition of the PI3K/AKT pathways increased the antitumor effects of proteasome inhibitors [31] . By contrast, activation of the JNK/c-Jun pathway was closely associated with growth inhibition in human glioblastoma cells [5] .…”

EGFR and NF-κB: partners in cancer

“…Bortezomib attenuated the cytotoxic effects of cetuximab and radiation by limiting EGFR degradation through the proteasome [66]. Proteasome inhibition actually enhanced MAPK, AKT, and STAT3 prosurvival pathways through both EGFR-dependent and -independent mechanisms [67]. These studies highlighted the need to design new combinatorial approaches by using a morespecific NF-kB inhibitor than bortezomib, which blocks the degradation of IkBa as well as of numerous other proteins, including key oncogenic products [68].…”

Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction

“…The antitumor properties of NPI-0052 have been evaluated in a wide range of nonclinical studies including in vitro and in vivo models for a wide range of solid tumors and hematologic malignancies (Chauhan et al, 2005(Chauhan et al, , 2008Cusack et al, 2006;Ruiz et al, 2006;Miller et al, 2007;Roccaro et al, 2008;Sloss et al, 2008). NPI-0052 as a single agent has shown advantages compared to conventional proteasome inhibitors such as bortezomib and MG-132 with regards to higher speed and duration of action, wider spectrum of inhibitory effects to the 20S proteasome, greater …”