Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis

Abstract

Proteasome inhibitors, such as bortezomib (BTZ), are highly effective and widely used treatments for multiple myeloma. One proposed reason for myeloma cells’ exceptional sensitivity to proteasome inhibition is that they produce and continually degrade unusually large amounts of abnormal immunoglobulins. We, therefore, hypothesized that, heat shock may also be especially toxic to myeloma cells by causing protein unfolding, increasing further the substrate load on proteasomes, and, thus, putting further stress on their capacity for protein homeostasis. After a shift from 37 to 43 °C, all four myeloma lines studied underwent extensive apoptosis in 4 h, unlike 13 nonmyeloma cell lines, even though the myeloma cells induced heat-shock proteins and increased protein degradation similar to other cells. Furthermore, two myeloma lines resistant to proteasome inhibitors were also more resistant to 43 °C. Shifting myeloma cells to 43, 41, or 39 °C (which was not cytotoxic) dramatically increased their killing by proteasome inhibitors and inhibitors of ubiquitination or p97/VCP. Combining increased temperature with BTZ increased the accumulation of misfolded proteins and substrate load on the 26S proteasome. The apoptosis seen at 43 °C and at 39 °C with BTZ was mediated by caspase-9 and was linked to an accumulation of the proapoptotic Bcl-2-family member Noxa. Thus, myeloma cells are exceptionally sensitive to increased temperatures, which greatly increase substrate load on the ubiquitin-proteasome system and eventually activate the intrinsic apoptotic pathway. Consequently, for myeloma, mild hyperthermia may be a beneficial approach to enhance the therapeutic efficacy of proteasome inhibitors.

Emerging roles of DYRK2 in cancer

“…In that sense, a DYRK2 inhibitor induced cytotoxicity even in MM cells resistant to proteasome inhibitors ( 25 , 26 ), suggesting that in fact DYRK2 inhibition might be targeting different complementary pathways. This observation was further echoed by a recent study showing that MM cells were extremely sensitive to increased temperatures and heat shock ( 54 ). In fact, combining heat shock with proteasome inhibitors led to higher accumulation of misfolded proteins leading to acute proteotoxic stress and apoptosis in the myeloma cells ( 54 ).…”

“…This observation was further echoed by a recent study showing that MM cells were extremely sensitive to increased temperatures and heat shock ( 54 ). In fact, combining heat shock with proteasome inhibitors led to higher accumulation of misfolded proteins leading to acute proteotoxic stress and apoptosis in the myeloma cells ( 54 ). Because cancer cells harbor significantly higher misfolded proteins than normal cells, targeting DYRK2 could indeed tip the scales for proteostasis in malignant cells and provide a significant therapeutic window for targeting specific cancers.…”

“…Intriguingly, MM cells are highly sensitive to DYRK2 inhibition irrespective of p53 status ( 25 , 26 ). Because DYRK2 inhibition in myeloma tips the balance of proteotoxic stress ( 26 , 54 ), all cells whether p53 WT (such as cell line MM.1S) or mutated (such as cell lines RPMI8226 and U266B1) die ( 26 ). This suggests that in myeloma, the role of DYRK2 as an oncogenic driver probably plays a far greater role than its tumor-suppressor function potentiated by p53 phosphorylation.…”

Advances in Proteasome Enhancement by Small Molecules

“…Proteasome inhibition results in the accumulation of I κ B [ 43 , 44 , 45 , 46 , 47 , 48 ], cyclin-dependent kinase (CDK) inhibitor p21 [ 43 , 49 , 50 ], tumor suppressor p53, and other pro-apoptotic proteins [ 51 , 52 , 53 ]. The exceptional increase in apoptosis of certain multiple myeloma cells when treated with proteasome inhibitors has also been linked to an increase in protein unfolding and increasing substrate load on the proteasomes [ 54 , 55 ]. In addition, proteasome inhibition leads to lethal shortage of amino acids in the cells, which are the building blocks for cells to make new proteins.…”

Novel insights into the impact of the SUMOylation pathway in hematological malignancies (Review)

“…Thus, the present review focused on hematological malignancies (leukemias, lymphomas and myelomas), with an emphasis on multiple myeloma (MM), a genetically heterogeneous plasma cell malignancy characterized by massive secretion of (in-)complete monoclonal antibodies, which is prone to recurrence and relapse ( 14 , 15 ). Balancing protein homeostasis and post-translational regulation is vital for the survival of MM cells ( 16 ). This review describes the known functions of the SUMOylation and deSUMOylation pathways and summarizes the mechanisms of SUMOylation-mediated tumorigenesis and drug resistance.…”