| 1. |
- Corman, Alba, et al.
(författare)
-
A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
- 2021
-
Ingår i: PLoS biology. - : Public library of science. - 1544-9173 .- 1545-7885. ; 19:5
-
Tidskriftsartikel (refereegranskat)abstract
- We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.
|
|
| 2. |
- Kanellis, Dimitris C., et al.
(författare)
-
The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output
- 2021
-
Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:32
-
Tidskriftsartikel (refereegranskat)abstract
- Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3's tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint-mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3's unexpected role in RiBi, with implications for cancer pathogenesis and treatment.
|
|
| 3. |
- Neddermeyer, Anne, et al.
(författare)
-
A new mutant NPM1/IDH2R140- and PML-RARA-associated lncRNA MALNC plays a role in AML biology, prognosis and drug response
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by poor prognosis that requires better understanding of its disease biology and new tools for suitable risk stratification and effective treatments. Long non-coding RNAs (lncRNAs) are involved in numerous molecular mechanisms, are implicated in tumor biology and can serve as clinical biomarkers, yet their role remains mostly unclear in AML. In this study, the aim was to discover and characterize lncRNAs implicated in AML and to describe their role in AML biology. Further aims were to explore their use as prognostic or predictive biomarkers. Using whole-transcriptome analysis, a novel lncRNA, here named MALNC, was identified. MALNC had elevated expression in two large AML cohorts compared to normal CD34+ cells. Clinical correlation analyses indicated that MALNC was almost uniquely expressed in patients with PML-RARA fusion gene and with co-mutated isocitrate dehydrogenase-2 R140 and nucleophosmin-1 (IDH2R140/NPM1). MALNC expression was specifically high at the promyelocytic stage and decreased with maturation in leukemic and normal cells. High MALNC expression associated independently with better overall survival. CRISPR-Cas9-knockout in promyelocytic cell lines impaired proliferation, colony formation and all-trans retinoic acid (ATRA)-induced differentiation. Also, MALNC-knockout dramatically sensitized cells to arsenic trioxide (ATO), ATO-ATRA combinatorial and Bcl-2-inhibitor venetoclax treatment as well as associated with cyclin-dependent kinase (Cdk)-inhibitor resistance. In conclusion, MALNC is overexpressed in certain subgroups of AML and could play a role during normal and leukemic hematopoietic maturation. Furthermore, it correlates with response to anti-leukemic drugs, which suggests a role as a predictive marker to drug response and survival in AML.
|
|
