Infliction of proteotoxic stresses by impairment of the unfolded protein response or proteasomal inhibition as a therapeutic strategy for mast cell leukemia

Abstract

The intensity and duration of endoplasmic reticulum (ER) stress converts the unfolded protein response (UPR) from an adaptive into a terminal response. The first regulates homeostasis, the latter triggers apoptosis. Cells that rapidly proliferate and possess developed secretory capabilities, such as leukemia cells, depend on an efficiently operating UPR to maintain proteostasis. Activation of terminal UPR by either blockade of adaptive UPR or exaggeration of ER stress has been explored as a novel approach in cancer therapy. For mast cell leukemia (MCL) the efficacy of both approaches, by utilizing the KIT V560G,D816V-positive MCL cell line HMC-1.2, was investigated. We show that HMC-1.2 cells display a tonic activation of the IRE1α arm of the UPR, which constitutively generates spliced XBP1. Inhibition of IRE1α by different types of inhibitors (MKC-8866, STF-083010, and KIRA6) suppressed proliferation at concentrations needed for blockade of IRE1α-mediated XBP1 splicing. At higher concentrations, these inhibitors triggered an apoptotic response. Blocking the proteasome by bortezomib, which confers an exaggerated UPR, resulted in a marked cytotoxic response. Bortezomib treatment also caused activation of the kinase JNK, which played a pro-proliferative and anti-apoptotic role. Hence, the combination of bortezomib with a JNK inhibitor synergized to induce cell death. In summary, the UPR can be addressed as an effective therapeutic target against KIT D816V -positive MCL.

Proteotoxic Stress and Cell Death in Cancer Cells

“…Clearly, impacting these adaptive mechanisms has important consequences to the survival of cancer cells [209,210]. This dependence has attracted interest in developing therapeutic approaches aimed at switching-off these adaptations and thus unleashing all the dramatic consequences of the unresolved proteotoxic stress [210][211][212][213][214][215][216][217][218]. In some circumstances, adaptations to proteotoxic stress can favor the resistance to other therapeutic regiments, as observed for HSF1 and the resistance to the receptor tyrosine kinase (RTK) inhibitor lapatinib in breast cancer [219].…”

EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

“…Upon activation, IRE1α cleaves the mRNA encoding for the X-box binding protein (XBP1), removing a 26 nucleotide intron and prompting the translation of spliced XBP1 (XBP1s). The latter is a transcription factor and controls the expression of a large number of ER chaperones and proteins involved in ER-associated degradation (ERAD) including, for instance, DnaJ Heat Shock Protein Family (Hsp40) Member B9 (DNAJB9) [10,11,12]. In addition, the IRE1α RNase domain directly degrades diverse mRNAs and microRNAs through a process termed “Regulated IRE1-Dependent Decay” (RIDD), regulating inflammation and apoptosis amongst others [13,14,15,16].…”

ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

“…Interestingly, stronger inhibition of IRE1α induced a switch from adaptive to terminal UPR. Enhancing ER stress by pharmacological inhibition of proteasome activity with bortezomib also induced terminal UPR in this model [ 168 ]. In Philadelphia-positive ALL, pharmacological inhibition of IRE1α with MKC-8866 also appeared able to reorient the initial cytoprotective UPR program towards cell death induction when combined with the inhibition of BCR-ABL1 with nilotinib [ 169 ].…”