Abstract
Multiple myeloma is a clonal plasma cell disorder in which growth and proliferation are linked to a variety of growth factors, including insulin-like growth factor type I (IGF-I). Bortezomib, the first-in-class proteasome inhibitor, has displayed significant antitumor activity in multiple myeloma. We analyzed the impact of IGF-I combined with proteasome inhibitors on multiple myeloma cell lines in vivo and in vitro as well as on fresh human myeloma cells. Our study shows that IGF-I enhances the cytotoxic effect of proteasome inhibitors against myeloma cells. The effect of bortezomib on the content of proapoptotic proteins such as Bax, Bad, Bak, and BimS and antiapoptotic proteins such as Bcl-2, Bcl-XL, XIAP, Bfl-1, and survivin was enhanced by IGF-I. The addition of IGF-I to bortezomib had a minor effect on NF-κB signaling in MM.1S cells while strongly enhancing reticulum stress. This resulted in an unfolded protein response (UPR), which was required for the potentiating effect of IGF-I on bortezomib cytotoxicity as shown by siRNA-mediated inhibition of GADD153 expression. These results suggest that the high baseline level of protein synthesis in myeloma can be exploited therapeutically by combining proteasome inhibitors with IGF-I, which possesses a "priming" effect on myeloma cells for this family of compounds.
Highlights
Cancer cells differ from normal cells by the abnormal use or activation of certain metabolic pathways such as anaerobic glycolysis [1]
These stimulatory and protective roles of the microenvironment partly rely on the local production of growth factors such as interleukin-6 (IL-6) and insulinlike growth factor 1 (IGF-I) and have prompted the evaluation of targeted therapies aiming to block the activity of these proteins [2, 3]
Our results suggest that insulin-like growth factor type I (IGF-I) signaling enhances the cytotoxicity of proteasome inhibitors in multiple myeloma cells via several mechanisms, including the induction of a unfolded protein response (UPR)
Summary
IGF-I potentiates the apoptotic effects of bortezomib and other proteasome inhibitors in vitro, ex vivo, and in vivo. To evaluate the transcriptional activity of NF-kB, we conducted a pangenomic analysis of MM.1S cells exposed to bortezomib in the presence or absence or IGF-I and did not observe any variation in the 11 genes of the NF-kB score previously described [32] nor in other NF-kB–related genes (Supplementary Table S2) These results suggest that the potentiating effect of bortezomib by IGF-I does not involve NF-kB signaling. To determine whether the UPR was required for IGF-I– mediated enhancement of the cytotoxicity of bortezomib, we transfected siRNA directed against GADD153 into MM.1S cells This transfection efficiently decreased GADD153 (CHOP) protein expression (Supplementary Fig. S6).
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