MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFκB Activation in Breast Cancer

Abstract

MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na þ -coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFkB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17-induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na þ -coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFkB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug.

Efficacy of bortezomib in sarcomas with high levels of MAP17 (PDZK1IP1)

“…Similar data could be observed in the AA and AW cell lines, where the overexpression of MAP17 reduces NFκB activation and autophagy (Figure 6B, Supplementary Figure S4A). Moreover, we observed that MAP17 prevents the cytoprotective activation of NFκB and autophagy induced by bortezomib (Figure 6C, Supplementary Figure S4B) in sarcoma cell lines, a finding that has been reported previously for breast tumor cells [29]. Therefore, the inhibition of these protective pathways induced by MAP17 may explain the increase in sensitivity to bortezomib found in vivo .…”

“…We have previously shown that MAP17 prevents cytoprotective NFκB activation and autophagy induced by bortezomib in breast tumor cells [29]. Therefore, we have tested whether these molecular markers correlate also in our PDX models prior to treatment (Figure 6A).…”

“…To this end, we planned to test bortezomib, which showed efficacy in breast tumor cells if MAP17 is overexpressed [29]. Thus, we first analyzed the role of MAP17 levels in sarcoma cell lines.…”

“…MAP17 maintains a functional relationship with the proteasomal degradation pathway [29]. Used as a “seed”, MAP17 was found to be linked to proteins related to degradation pathways, mainly ubiquitination- and sumoylation-related pathways.…”

“…Therefore, MAP17 is not only a marker for stage and malignant status but also may be a marker of response to therapies, inducing oxidative stress. In breast tumor cells, the MAP17 expression level determines the sensitivity to bortezomib by inhibiting the cytoprotective effects resulting from bortezomib-induced NFκB nuclear translocation and autophagy [29]. Furthermore, the inhibition of oxidative stress abolishes the MAP17-induced sensitivity to bortezomib.…”