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Proteasome inhibition leads to dephosphorylation and downregulation of protein expression of members of the Akt/mTOR pathway in MCL

Leukemia volume 26, pages 2442–2444 (2012)Cite this article

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As previously shown bortezomib exhibits significant antilymphoma activity not only in the well-characterized MCL (mantle cell lymphoma) cell lines, but also in the T-cell leukemia cell line Jurkat, and the follicular B-cell lymphoma cell line lymphoma Karpas 422. To identify common patterns of downstream events in MCL following bortezomib exposure, protein expression analysis and mRNA expression analysis were performed and compared with cell proliferation, cell viability and apoptosis.

Another downstream target of the PI3K/Akt pathway is mammalian target of rapamycin (mTOR). The mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.4 mTOR is a serine–threonine kinase downstream of Akt, which catalytic subunit consists of the two multi-protein complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor), which have distinct substrates and mechanisms of activation.4 Analogs of rapamycin, a mTOR inhibitor, which blocks some of the mTORC1 functions but does not have an effect on mTORC2, has already been shown highly active in clinical trials 4 and has been recently registered for the treatment of relapsed MCL in Europe. In our study we could show that beside moderate downregulation and dephosphorylation of mTOR bortezomib downregulated and dephosphorylated Raptor (Ser792), as well as Rictor (Thr1135) (Figures 2e and f). This data indicate that bortezomib has an effect on both mTOR complexes, mTORC1 and mTORC2 (Figure 1 and Figures 2e and ). Accordingly bortezomib not only induced cell cycle arrest, as do rapamycin analogs,4 but also apoptosis. Thus, bortezomib acts on both complexes simultaneously and the negative feedback loop activating Akt via mTORC2 due to inhibition of mTORC1, described for rapamycin and analogs,4 will be inhibited (Figure 1).

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Authors and Affiliations

  1. Department of Medicine III, University Hospital Grosshadern/LMU, Munich, Germany

    G Hutter, Y Zimmermann, M Rieken, W Hiddemann & M Dreyling

  2. CCG Leukemia, Helmholtz Zentrum, Munich, Germany

    G Hutter, Y Zimmermann, M Rieken, W Hiddemann & M Dreyling

  3. Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany

    E Hartmann & A Rosenwald

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  1. G Hutter
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Correspondence to G Hutter.

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The coauthor M Dreyling is a member of the scientific advisory board of Janssen and received speakers honoraria and support of investigator-initiated trials by Janssen.

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Hutter, G., Zimmermann, Y., Rieken, M. et al. Proteasome inhibition leads to dephosphorylation and downregulation of protein expression of members of the Akt/mTOR pathway in MCL. Leukemia 26, 2442–2444 (2012). https://doi.org/10.1038/leu.2012.118

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