No abstract

Intensive protein synthesis is a unique and differential trait of the multiple myeloma (MM) cells. Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin‑induced MM cell death with emphasis on eIF4E translation initiation factor. We showed tetraspanins attenuated peIF4E and its targets [c‑Myc, cyclin D1 (cycD1)]; eIF4E attenuation was Akt-dependent. eIF4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti‑viral drug and competitive eIF4E inhibitor ribavirin (RBV) deleteriously affected MM cells in a similar manner to the overexpression of tetraspanins. Furthermore, combined application of RBV and velcade had a synergistic anti‑MM effect. Our results demonstrate that breach of proteostasis via eIF4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic.

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Patients presenting with advanced-stage NSCLC have poor prognosis, while metastatic spread accounts for >70 % of patient's deaths. The major advances in the treatment of lung cancer have brought only minor improvements in survival; therefore, novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of bone marrow MSCs (BM-MSCs) from normal donors on NSCLC cell lines with special emphasis on translation initiation mechanism in the crosstalk. We cultured NSCLC cell lines with BM-MSC conditioned media (i.e., secretome) and showed deleterious effects on the cells' proliferation, viability, death, and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression [eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic translation initiation factor 4GI (eIF4GI)], their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's mitogen-activated protein kinase (MAPK) signaling pathway, downregulated the cell migration, and diminished translation initiation factors' levels. Taken together, our study demonstrates that there is direct dialogue between the BM-MSCs' secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We suggest that therapeutic approach that will sabotage this dialogue, especially in the BM microenvironment, may diminish lung cancer metastatic spread and morbidity and improve the patient's life quality.

Multiple myeloma (MM) cells' interaction with the bone marrow (BM) microenvironment critically hinders disease therapy. Previously, we showed that MM co-culture with BM-mesenchymal stem cells (MSCs) caused co-modulation of translation initiation (TI) and cell phenotype and implicated secreted components, specifically microvesicles (MVs). Here, we studied the role of the BM-MSCs [normal donors (ND) and MM] secreted MVs in design of MM cells' phenotype, TI and signaling. BM-MSCs' MVs collected from BM-MSCs (MM/ND) cultures were applied to MM cell lines. After MVs uptake confirmation, the MM cells were assayed for viability, cell count and death, proliferation, migration, invasion, autophagy, TI status (factors, regulators, targets) and MAPKs activation. The interdependence of MAPKs, TI and autophagy was determined (inhibitors). ND-MSCs MVs' treated MM cells demonstrated a rapid (5 min) activation of MAPKs followed by a persistent decrease (1-24 h), while MM-MSCs MVs' treated cells demonstrated a rapid and continued (5 min-24 h) activation of MAPKs and TI (↑25-200%, P < 0.05). Within 24 h, BM-MSCs MVs were internalized by MM cells evoking opposite responses according to MVs origin. ND-MSCs' MVs decreased viability, proliferation, migration and TI (↓15-80%; P < 0.05), whereas MM-MSCs' MVs increased them (↑10-250%, P < 0.05). Inhibition of MAPKs in MM-MSCs MVs treated MM cells decreased TI and inhibition of autophagy elevated cell death. These data demonstrate that BM-MSCs MVs have a fundamental effect on MM cells phenotype in accordance with normal or pathological source implemented via TI modulation. Future studies will aim to elucidate the involvement of MVs-MM receptor ligand interactions and cargo transfer in our model.