bims-hypusi 2026-10-25 papers

Issue of 2026–10–25
three papers selected by
Sebastian J. Hofer, Max Delbrück Center

Mol Oncol. 2026 Oct 21.

A role for eIF5A in translational control of stress-inducible proteins in multiple myeloma cell lines.

Demi Both, Ingrid A M Derks, Raphaël Vanleyssem, Marine Leclercq, Najla El Hachem, Pierre Close, Eric Eldering, Marco Vincent Haselager.

Impaired protein folding in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR), which can induce apoptosis during prolonged ER stress. ER stress is therapeutically targeted in plasma cell malignancies, such as multiple myeloma (MM), but these treatments remain noncurative, and UPR signaling in B-cell malignancies is incompletely understood. A targeted CRISPR-Cas9 screen in RPMI-8226 cells exposed to thapsigargin identified known ER stress regulators (XBP1, IRE1, and calreticulin) and the translation factor eIF5A (eukaryotic translation initiation factor 5A), whose role in ER stress remains unclear. Competition assays showed that eIF5A depletion is detrimental under basal conditions but confers a proliferation advantage during thapsigargin treatment. Inducible EIF5A knockouts confirmed reduced sensitivity specifically to thapsigargin, loss of eIF5A had no or sensitizing effects on cell death induced by other ER stress drugs. Polysome profiling revealed that not general translation, but the translation of specific mRNA transcripts coding for UPR components and apoptotic proteins was affected by eIF5A depletion. Correspondingly, EIF5A KO cells showed reduced thapsigargin-induced UPR activation. In conclusion, these findings indicate that loss of eIF5A alters the stress response in MM cells.

Keywords: ER stress; UPR; apoptosis; eIF5A; multiple myeloma; translation

DOI: https://doi.org/10.1002/1878-0261.70328

Amino Acids. 2026 Sep 16. pii: 60. [Epub ahead of print]58(1):

Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells.

Hwudaurw Chen, David E Stringer, Haiyan Cui, Eugene W Gerner, Natalia A Ignatenko.

Oncogenic mutations in the K-RAS small GTPase occur in more than 90% of human PDACs and cause dysregulation of multiple metabolic pathways, including polyamine metabolism. The goal of this study was to determine whether blocking polyamine synthesis with the irreversible inhibitor α-difluoromethylornithine (DFMO) provides a valid approach to targeting metabolic dependency in mutant K-RAS pancreatic tumors, compared with direct suppression of the oncogenic K-RAS protein. The anti-tumor activity of DFMO was evaluated in vitro and in vivo in the MIA PaCa-2 pancreatic cell line (K-RASG12C) and its isogenic clonally selected line M-27, which does not express a functional GTP-bound RAS protein. MIA PaCa-2 and M-27 cells had comparable intracellular polyamine levels, and DFMO treatment effectively suppressed total polyamine levels in both cell lines (p < 0.01). DFMO reduced the protein levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and RAS-like small GTPase A (RalA) but induced the phosphoinositide 3-phosphate kinase (PI3K) signaling pathway. Additionally, the intracellular levels of K-RAS and hypusinated eukaryotic initiation factor 5 A (eIF5AHyp) proteins were suppressed in DFMO-treated MIA PaCa-2 cells. DFMO therapy regimen (500 mg/kg/day by oral gavage) significantly improved survival rates of SCID mice with orthotopically implanted MIA PaCa-2 cell line (MIA PaCa-2 control vs. MIA PaCa-2 DFMO, p = 0.0184), with median survival time comparable to animals implanted with M-27 cell line (MIA PaCa-2 control vs. M-27 control, p = 0.0204). DFMO treatment did not significantly improve survival of mice bearing M-27 tumors (M-27 control vs. M-27 DFMO, p = 0.6055). These data indicate that DFMO treatment suppresses pancreatic tumorigenesis driven by the mutant K-RAS oncogene similarly to the targeted elimination of the active GTP-bound RAS protein.

Keywords: Difluoromethylornithine; Hypusinated eIF5A; Pancreatic adenocarcinoma; Pancreatic orthotopic mouse model; Polyamines; RAS-like small GTPase A

DOI: https://doi.org/10.1007/s00726-026-03559-5

Sci Adv. 2026 Oct 23. 12(43): eaeg5840

Structural basis for start codon selection by eIF5-mimic proteins.

Ximena Zottig, Chun-Ying Huang, Zahra Seraj, Nikolaus Grigorieff, Andrei A Korostelev.

Start codon selection extensively regulates the cellular proteome and is implicated in cancer and other diseases. The eIF5-mimic proteins (5MPs: 5MP1/BZW2 and 5MP2/BZW2) restrict non-AUG start codon usage and thereby reprogram proteoform expression from mRNAs with alternative start sites, such as the oncogenic c-Myc. Here, using in extracto cryo-electron microscopy (cryo-EM) and biochemical assays, we report how 5MP represses translation dependent on the sequence context at start codons. Cryo-EM structures of 48S preinitiation complexes (PICs) reveal 5MP1 bound at the A site of the small ribosomal subunit. 5MPs act as initiation factors that stabilize an open PIC conformation, promoting mRNA scanning and inhibiting initiation at suboptimal start codons. We propose to designate 5MP as eIF1S (eukaryotic initiation factor 1 scanning). These findings reveal the structural basis for proteome modulation by 5MPs and may help correct dysregulated translation in disease.

DOI: https://doi.org/10.1126/sciadv.aeg5840