DangER: protein ovERload. Targeting protein degradation to treat myeloma

Abstract

Myeloma is a malignancy of the antibody-producing plasma cells and, as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome. More recently, the role of autophagy has been recognized in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways.

Figure 1.

Relationship between the ER stress and autophagy pathways. The three ER stress sensor molecules, PERK, IRE1 and ATF6, are held in an inactive state by GRP78. The presence of unfolded protein results in their release and subsequent activation. The PERK and IRE1 branches are the most important for ER stress-induced autophagy: in the IRE1 branch, Bcl2 is phosphorylated by JNK, resulting in the release of Bcl2 from a complex with Beclin1 thus allowing autophagy to be activated. In the PERK branch, ATF4 and CHOP both lead to the upregulation of key autophagy genes. CHOP can also inhibit Akt via Trb3, thereby allowing autophagy activation.

Figure 2.

Schematic overview of the autophagy pathway. Initiation of autophagy results in the formation of the ULK1 complex, consisting of ULK1, FIP200, Atg13 and Atg17, which is negatively regulated by mTOR. Atg1 also acts to recruit additional Atg proteins to the phagophore. Vps34 forms a core complex with Beclin1 and p150 and produces PI3P for membrane formation. The Atg5-Atg12-Atg16 complex is formed by the combined action of Atg7 and Atg10 while processing of LC3 is accomplished by Atg4, Atg3 and Atg7. The completed autophagosome contains cytosolic proteins and/or organelles and subsequently fuses with lysosmes. The enzymes present in lysosomes degrade the autophagosome contents and this material is then recycled back to the cell. 3-MA: 3-methyladenine.

Figure 3.

Relationship between the autophagy and proteasome pathways. Proteasome inhibition by bortezomib or MG132 results in the compensatory upregulation of the autophagy pathway, whereas inhibition of the autophagy pathway by bafilomycin A1, 3-MA or chloroquine inhibits the proteasome.