Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

Abstract

Enhanced protein synthesis capacity is associated with increased tumor cell survival, proliferation, and resistance to chemotherapy. Cancers like multiple myeloma (MM), which display elevated activity in key translation regulatory nodes, such as the PI3K/ mammalian target of rapamycin and MYC-eukaryotic initiation factor (eIF) 4E pathways, are predicted to be particularly sensitive to therapeutic strategies that target this process. To identify novel vulnerabilities in MM, we undertook a focused RNAi screen in which components of the translation apparatus were targeted. Our screen was designed to identify synthetic lethal relationships between translation factors or regulators and dexamethasone (DEX), a corticosteroid used as frontline therapy in this disease. We find that suppression of all three subunits of the eIF4F cap-binding complex synergizes with DEX in MM to induce cell death. Using a suite of small molecules that target various activities of eIF4F, we observed that cell survival and DEX resistance are attenuated upon eIF4F inhibition in MM cell lines and primary human samples. Levels of MYC and myeloid cell leukemia 1, two known eIF4F-responsive transcripts and key survival factors in MM, were reduced upon eIF4F inhibition, and their independent suppression also synergized with DEX. Inhibition of eIF4F in MM exerts pleotropic effects unraveling a unique therapeutic opportunity.silvestrol | hippuristanol | eIF4A | RNAi screening

Targeting RNA helicases in cancer: The translation trap

“…In line with these observations, the Silvestrol analogues CR-1-31-B and FL-3 synergize with vemurafenib in melanoma xenografts[86]. In addition, Silvestrol was found to synergize with doxorubicin[83], daunarubicin[92], rapamycin[93] and dexamethason[76]. In a similar way, Hippurastinol overcomes resistance in PI3K/Akt/mTOR driven tumors and synergizes with the Bcl-2 family inhibitor ABT-373 and resensitizes Eμ-Myc lymphomas to DNA damaging agents [94].…”

“…Knockdown experiments of eIF4A reduced proliferation and induced cell death in cancer cell lines[17, 76]. In addition, in murine models overexpression of eIF4A accelerated leukemia development[22].…”

“…In addition, in murine models overexpression of eIF4A accelerated leukemia development[22]. Several eIF4A inhibitors are currently under development and are thought to exert their effect by translational inhibition of key oncogenes (e.g., c-MYC )[21–23, 76] (Table 1). …”

The biology of DHX9 and its potential as a therapeutic target

“…The Arf −/− Eμ- myc /Bcl-2 model recapitulates several clinically relevant features of non-Hodgkin's lymphomas; DHX9 may therefore show promise as a candidate target to suppress in combination with ABT-737 or its derivatives. Knockdown of DHX9 also synergizes with the glucocorticoid dexamethasone in human multiple myeloma cell lines [82, 194], suggesting a potential for targeting DHX9 in multiple myeloma as well.…”

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

“…shRNA (Lentivirus) Translation initiation factor eIF4F is one of the best-studied MYC effectors and a downstream target of the PI3K/mTOR pathway. shRNA-mediated knockdown of three subunits of the eIF4F cap-binding complex enhanced myeloma cell death in combination with dexamethasone, a corticosteroid used as frontline therapy in MM [88] Plasmid-based shRNA (Electroporation)…”