Bevacizumab attenuates major signaling cascades and eIF4E translation initiation factor in multiple myeloma cells

• Published in: Laboratory investigation Vol. 92; no. 2; pp. 178 - 190
• Main Authors: Attar-Schneider, Oshrat, Drucker, Liat, Zismanov, Victoria, Tartakover-Matalon, Shelly, Rashid, Gloria, Lishner, Michael
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.02.2012; Nature Publishing Group US; Nature Publishing Group
• Subjects: Aged; Aged, 80 and over; Angiogenesis Inhibitors - pharmacology; Antibodies, Monoclonal, Humanized - pharmacology; Autophagy - drug effects; avastin; Bevacizumab; Biological and medical sciences; Biotechnology; Cell Cycle; Cell Line, Tumor; eIF4E; Eukaryotic Initiation Factor-4E - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunohistochemistry; Immunopathology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; multiple myeloma; Multiple Myeloma - enzymology; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Pathology; research-article; Signal Transduction - drug effects; translation initiation; Vascular Endothelial Growth Factor A - antagonists & inhibitors; VEGF; translation initiation; eIF4E; multiple myeloma; VEGF; avastin; Antineoplastic agent; Immunopathology; Biotechnology; Initiation factor; Translation initiation; Malignant hemopathy; Monoclonal antibody; Myeloma; Bevacizumab; Immunomodulator; Signal transduction; Vascular endothelium growth factor; Immunoglobulinopathy; Lymphoproliferative syndrome; Clinical biology; Antiangiogenic agent; Cell; Cancer
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2011.162

Multiple myeloma (MM), a malignancy of plasma cells, remains fatal despite introduction of novel therapies, partially due to humoral factors, including vascular endothelial growth factor (VEGF), in their microenvironment. The aim of this study was to explore the efficacy of anti-VEGF treatment with bevacizumab directly on MM cells. Particular attention was directed to the affect of VEGF inhibition on protein translation initiation. Experiments were conducted on MM cells (lines, bone marrow (BM) samples) cultured on plastic. Inhibition of VEGF was achieved with the clinically employed anti-VEGF antibody, bevacizumab, as a platform and its consequences on viability, proliferation, and survival was assessed. VEGF downstream signals of established importance to MM cell biology were assayed as well, with particular emphasis on translation initiation factor eIF4E. We showed that blocking VEGF is deleterious to the MM cells and causes cytostasis. This was evidenced in MM cell lines, as well as in primary BM samples (BM MM). A common bevacizumab-induced attenuation of critical signaling effectors was determined: VEGFR1, mTOR, c-Myc, Akt, STAT3, (cell lines) and eIF4E translation initiation factor (lines and BM). ERK1/2 displayed a variegated response to bevacizumab (lines). Utilizing a constitutively Akt-expressing MM model, we showed that the effect of bevacizumab on viability and eIF4E status is Akt-dependent. Of note, the effect of bevacizumab was achieved with high concentrations (2 mg/ml), but was shown to be specific. These findings demonstrate that bevacizumab has a direct influence on major pathways critically activated in MM that is independent from its established effect on angiogenesis. The cytostatic effect of VEGF inhibition on MM cells underscores its potential in combined therapy, and our findings, regarding its influence on translation initiation, suggest that drugs that unbalance cellular proteostasis may be particularly effective.