Publication details

A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis

Authors

BESSE Lenka BESSE Andrej MENDEZ-LOPEZ Max VAŠÍČKOVÁ Kateřina SEDLÁČKOVÁ Miroslava VAŇHARA Petr KRAUS Marianne BADER Jurgen FERREIRA Renan B. CASTELLANO Ronald K. LAW Brian K. DRIESSEN Christoph

Type Article in Periodical
Magazine / Source Haematologica
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.3324/haematol.2018.207704
Keywords metabolic switch; proteasome inhibitor; multiple myeloma
Description Proteasome inhibitors (PI) have evolved as the central backbone of treatment for multiple myeloma (MM), with first-in-class bortezomib and second- and third-generation PI, carfilzomib and ixazomib, having been approved for this indication. Proteasome inhibition disrupts the unfolded protein response to resolve excessive endoplasmic reticulum stress, but also leads to massive metabolic changes manifested by the induction of amino acid biosynthesis, an anti-oxidant response, lipogenesis and an increase in protein folding. In this sense, PI represent a unique class of drugs targeting cancer cell metabolism by affecting the balance between protein biosynthesis, folding and destruction. However, the adaptive changes in MM cell metabolism may provide the basis of resistance to PI, as high glycolytic activity or rewiring glucose metabolism is associated with bortezomib resistance in MM.