RETRACTED ARTICLE: Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

Abstract

Protein translation is inhibited by the unfolded protein response (UPR)-induced eIF-2α phosphorylation to protect against endoplasmic reticulum (ER) stress. In addition, we found additional inhibition of protein translation due to diminished mTORC1 activity in ER-stressed multiple myeloma (MM) cells. However, c-myc protein levels and myc translation was maintained. To ascertain how c-myc was maintained, we studied myc IRES function which does not require mTORC1 activity. Myc IRES activity was upregulated in MM cells during ER stress induced by thapsigargin, tunicamycin or the myeloma therapeutic bortezomib. IRES activity was dependent upon upstream MAPK and MNK1 signaling. A screen identified hnRNP A1 (A1) and RPS 25 as IRES-binding trans factors required for ER stress-activated activity. A1 associated with RPS25 during ER stress and this was prevented by a MNK inhibitor. In a proof of principle, we identified a compound that prevented binding of A1 to the myc IRES and specifically inhibited myc IRES activity in MM cells. This compound, when used alone, was not cytotoxic nor did it inhibit myc translation or protein expression. However, when combined with ER stress inducers, especially bortezomib, a remarkable synergistic cytotoxicity ensued with associated inhibition of myc translation and expression. These results underscore the potential for targeting A1-mediated myc IRES activity in MM cells during ER stress.

Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma

“…2B). This was similar to our previous findings with multiple myeloma cell lines (21). However, as shown in Fig.…”

“…In our previous studies, we identified a small-molecule inhibitor of c-MYC IRES-dependent protein synthesis and demonstrated its efficacy in multiple myeloma when combined with inducers of the endoplasmic reticulum stress response (21). In this report, we have evaluated the action of this inhibitor in GBM and demonstrate significant synergistic anti-GBM activity of this inhibitor in combination with PP242.…”

“…The activation of this intrinsic pathway is dependent on SAPK2/p38-mediated activation of IRESdependent initiation of cyclin D1 and c-MYC mRNAs in GBM (20). Recently, we have described the therapeutic potential of targeting IRES-dependent c-MYC translation via the identification of a small molecule inhibitor that blocked c-MYC IRESmediated translation initiation (21).…”

“…1A), which specifically blocked c-Myc IRESmediated translation initiation by screening ϳ145,000 compounds in a yeast-based, three-hybrid assay targeting disruption of the ITAF hnRNP A1-IRES interaction (21). Because the cyclin D1 IRES utilizes hnRNP A1 as an ITAF, and its ability to initiate IRES-mediated translation is regulated in a similar manner as the c-MYC IRES, we determined whether FIGURE 1.…”

New frontiers in translational control of the cancer genome

“…These mRNAs possess distinct cis -regulatory elements in their 5′UTRs, such as IRES elements and uORFs, that direct transcript-specific translation in a manner compatible with reduced eIF4E and eIF2 activity. For example, hypoxia has been shown to induce a switch from cap-dependent to IRES-dependent translation that promotes tumour survival and angiogenesis through the ability of eIF4G to engage with IRES elements in specific mRNAs 175 , and IRES-mediated translation of select transcripts (for example, those encoding anti-apoptotic factors such as X-linked inhibitor of apoptosis protein (XIAP) and pro-angiogenic factors such as VEGFC) has been shown to support tumour growth and survival under stress conditions such as DNA damage and hypoxia 176–179 .…”