IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms

Abstract

IntroductionMultiple myeloma (MM) is a lethal plasma cell malignancy hallmarked by uncontrolled accumulation of monoclonal plasma cells in the bone marrow (BM). 1 There, the MM cells receive signals to survive and proliferate because of the existence of functional, mutual interactions through growth factors and adhesion molecules. 2 Importantly, these interactions also confer resistance to conventional therapies. 2 One of the most important growth factors involved in MM progression is insulin-like growth factor-1 (IGF-1). [3][4][5] This cytokine induces proliferation of both interleukin-6 (IL-6)-independent and -dependent cell lines, acts synergistically with IL-6, and protects MM cells from dexamethasone-induced apoptosis. 3 Moreover, IGF-1 also stimulates homing and production of angiogenic factors. 4,6,7 Binding to its receptor results in the activation of the Ras/Raf/MAPK (mitogen-activated protein kinase)/Erk (mainly triggering proliferation and secretion of vascular endothelial growth factor) and the PI-3K (phosphatidylinositol-3 kinase)/Akt pathways (involved mainly in antiapoptotic stimuli and mediating migration). 6,8 Both IGF-1 serum levels and IGF-1 receptor (IGF-1R) expression by the MM cells are important negative prognostic factors in MM. 9,10 The central role of IGF-1 in the MM pathophysiology is further supported by the encouraging preclinical results observed after targeting the IGF-1R with neutralizing antibodies or small molecule inhibitors. Previously, we demonstrated the efficacy of the IGF-1R tyrosine kinase inhibitor picropodophyllin to block the function of IGF-1R in vitro and in vivo and this both in murine and human MM cells. 11,12 The anti-MM activity of selective IGF-1R inhibitors was also confirmed with the use of the selective kinase inhibitor NVP-ADW742 in an orthotopic xenograft MM model. 4 Clinical trials examining the effect of both blocking antibodies and small molecule inhibitors are currently ongoing. 3 Bim (Bcl2like11) is a member of the BH3-only group of the Bcl-2 protein family and is a mediator of apoptosis. 13,14 Bim is a sensor of cell stress (withdrawal or inhibition of growth factor signaling or treatment with numerous cytotoxic agents) 13,15 and promotes apoptosis either indirectly by antagonizing the inhibitory function of the Bcl-2/Bcl-Xl members and thus liberating the innate cytotoxic Bax-like members or directly by activating the Bax-like members. 13 Three major isoforms of Bim are known: extra-long (BimEL), long (BimL), and short (BimS). All 3 isoforms induce apoptosis; the shortest being the most potent but the longest the most preponderant. 16 The proapoptotic activity of Bim seems to be controlled in various ways. In healthy cells, Bim is sequestered in its inactive form to the microtubular cytoskeleton or exists as inactive heterodimers (with antiapoptotic Bcl-2 family members) sequestered to the mitochondria. 17 In B and MM cells, Bim appears to be constitutively associated with Mcl-1. At induction of apoptosis, Bim is released from Mcl-1, thus activating ...

A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

“…Bim BH3 peptides prime neoplastic cells (including MM cells) for apoptosis induced by ABT-737, 41 but the therapeutic use of peptides presents a challenge. Alternatively, HDACIs upregulate Bim in tumor cells, including MM cells, 21,22 whereas BH3 mimetics (eg, ABT-737) unleash Bim from Bcl-2/Bcl-xL. 16 Interestingly, ABT-737 induced a modest but discernible decline in Bim levels, accompanied by increased Mcl-1 expression, 40 presumably representing compensatory responses to Bcl-2/Bcl-xL inhibition.…”

“…Current studies emphasize an important contribution of Bim to adaptive (or acquired) rather than intrinsic forms of bortezomib resistance in MM. They also describe a Bim-targeting strategy that combines HDACIs that upregulate Bim 21,22 with BH3 mimetics that unleash Bim from antiapoptotic proteins (eg, Bcl-2, Bcl-xL), 16 which may overcome such forms of bortezomib resistance.…”

“…20 Conversely, histone deacetylase inhibitors (HDACIs) upregulate Bim in tumor cells, including MM cells. 21,22 Among HDACIs, romidepsin and vorinostat have been approved for use in cutaneous T-cell lymphoma and peripheral T-cell lymphoma. 23 HDACI lethality involves multiple mechanisms, including oxidative injury, death receptor upregulation, antiapoptotic protein downregulation, Bim upregulation, and disabling of chaperone and DNA repair proteins, among others.…”

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

“…In many cancers, such as multiple myeloma, treatment with histone deacetylase inhibitors increases Bim expression and triggers apoptosis in a manner that is dependent (at least in part) on Bim. 43 In chronic myeloid leukemia, changes in Bim promoter methylation status are associated with differences in Bim gene expression. 44 As CBP is a cofactor in c-Myc-regulated Bim expression, and CBP mutations in the HAT domain are associated with tumor development, 40 we investigated whether epigenetic changes in the Bim promoter occur during bAR signalling.…”

An update on molecular biology and drug resistance mechanisms of multiple myeloma

“…Insulin-like growth factor (IGF-1) which is secreted by BMSC and osteoblasts induces growth, survival and migration of MM cells via MAPK and PI3K/Akt signaling pathway (De Bruyne et al, 2010). Activation of Akt leads to activation of the anti-apoptotic proteins such as Bcl-X L and Bcl-2 (Pollak, 2008).…”