Abstract
Growing evidence indicates that protein synthesis is deregulated in cancer onset and progression and targeting this process might be a selective way to combat cancers. While harmine is known to inhibit DYRK1A and intercalate into the DNA, tri-substitution was shown previously to modify its activity profile in favor of protein synthesis inhibition. In this study, we thus evaluated the optimized derivative CM16 in vitro anti-cancer effects unfolding its protein synthesis inhibition activity. Indeed, the growth inhibitory profile of CM16 in the NCI 60-cancer-cell-line-panel correlated with those of other compounds described as protein synthesis inhibitors. Accordingly, CM16 decreased in a time- and concentration-dependent manner the translation of neosynthesized proteins in vitro while it did not affect mRNA transcription. CM16 rapidly penetrated into the cell in the perinuclear region of the endoplasmic reticulum where it appears to target translation initiation as highlighted by ribosomal disorganization. More precisely, we found that the mRNA expression levels of the initiation factors EIF1AX, EIF3E and EIF3H differ when comparing resistant or sensitive cell models to CM16. Additionally, CM16 induced eIF2α phosphorylation. Those effects could explain, at least partly, the CM16 cytostatic anti-cancer effects observed in vitro while neither cell cycle arrest nor DNA intercalation could be demonstrated. Therefore, targeting protein synthesis initiation with CM16 could represent a new promising alternative to current cancer therapies due to the specific alterations of the translation machinery in cancer cells as recently evidenced with respect to EIF1AX and eIF3 complex, the potential targets identified in this present study.
Original language | English |
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Pages (from-to) | 25-35 |
Number of pages | 11 |
Journal | European Journal of Pharmacology |
Volume | 805 |
DOIs | |
Publication status | Published - 15 Jun 2017 |
Funding
The PhD of A.C. is financially supported by the Coordena\u00E7\u00E3o de Aperfei\u00E7oamento de Pessoal de Nivel Superior (Grant 0674-13/3; CAPES; Brazil). C.M. acknowledges the grant from the T\u00E9l\u00E9vie (7.4547.11F) (FRS-FNRS; Belgium). R.K. is a director of research with the Fonds National de la Recherche Scientifique (FRS-FNRS; Belgium) that supported the present project (#3.4525.11: Anti-canc\u00E9reux d\u00E9riv\u00E9s de l\u2032harmine from 2010 to 2014). Part of this study is also supported by the grant by the Belgian Brain Tumor Support (BBTS; Belgium). JP acknowledges grants from the Canadian Institutes of Health Research (MOP-106530 and MOP-115126). A.K. acknowledges the National Cancer Institute (CA186046-01A1) and Welch Foundation (AI-0045). The sources of funding had no role in the design of the study or in the collection, analysis, and interpretation of data or in writing the manuscript. Funding provided grant salaries to PhD students (AC and CM) and support for the consumables of the current work. We thank Mohsin Mssassi for his help during his stay in the Laboratoire of Canc\u00E9rologie et Toxicologie Exp\u00E9rimentale (ULB, Belgium).
Funders | Funder number |
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National Cancer Institute | R15CA186046 |
National Cancer Institute | |
Welch Foundation | AI-0045 |
Welch Foundation | |
Canadian Institutes of Health Research | MOP-115126, MOP-106530 |
Canadian Institutes of Health Research | |
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior | 0674-13/3 |
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior | |
Fonds de la Recherche Scientifique F.R.S.-FNRS | 3.4525.11 |
Fonds de la Recherche Scientifique F.R.S.-FNRS | |
Belgian Brain Tumor Support |
Keywords
- Beta-carboline
- Cancer
- Harmine
- Protein synthesis
- Translation initiation
- Humans
- Ribosomes/drug effects
- Antineoplastic Agents/chemistry
- RNA, Messenger/genetics
- Biological Transport
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Protein Biosynthesis/drug effects
- Harmine/chemistry
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