A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis

Annelise Carvalho, Jennifer Chu, Céline Meinguet, Robert Kiss, Guy Vandenbussche, Bernard Masereel, Johan Wouters, Alexander Kornienko, Jerry Pelletier, Véronique Mathieu

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langueAnglais
Pages25-35
Nombre de pages11
journalEuropean Journal of Pharmacology
Volume805
Les DOIs
étatPublié - 15 juin 2017

Empreinte digitale

norharman
Harmine
Protein Transport
Neoplasms
Protein Unfolding
Peptide Initiation Factors
Messenger RNA
Protein Synthesis Inhibitors
DNA
Cytostatic Agents
Protein Biosynthesis
Cell Cycle Checkpoints
In Vitro Techniques
Endoplasmic Reticulum

mots-clés

    Citer ceci

    Carvalho, Annelise ; Chu, Jennifer ; Meinguet, Céline ; Kiss, Robert ; Vandenbussche, Guy ; Masereel, Bernard ; Wouters, Johan ; Kornienko, Alexander ; Pelletier, Jerry ; Mathieu, Véronique. / A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis. Dans: European Journal of Pharmacology. 2017 ; Vol 805. p. 25-35
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    title = "A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis",
    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.",
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    A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis. / Carvalho, Annelise; Chu, Jennifer; Meinguet, Céline; Kiss, Robert; Vandenbussche, Guy; Masereel, Bernard; Wouters, Johan; Kornienko, Alexander; Pelletier, Jerry; Mathieu, Véronique.

    Dans: European Journal of Pharmacology, Vol 805, 15.06.2017, p. 25-35.

    Résultats de recherche: Contribution à un journal/une revueArticle

    TY - JOUR

    T1 - A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis

    AU - Carvalho,Annelise

    AU - Chu,Jennifer

    AU - Meinguet,Céline

    AU - Kiss,Robert

    AU - Vandenbussche,Guy

    AU - Masereel,Bernard

    AU - Wouters,Johan

    AU - Kornienko,Alexander

    AU - Pelletier,Jerry

    AU - Mathieu,Véronique

    PY - 2017/6/15

    Y1 - 2017/6/15

    N2 - 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.

    AB - 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.

    KW - Beta-carboline

    KW - Cancer

    KW - Harmine

    KW - Protein synthesis

    KW - Translation initiation

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