Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.

Integrative analysis of an endoplasmic reticulum stress‐related signature in multiple myeloma

“…Among them, XBP1 showed the highest number of interactions with other genes, indicating that XBP1 might have a central role in MM. XBP1 is a major regulator of the UPR and plasma cell differentiation and involved in the development and progression of myeloma 27 . Our finding was consistent with the research mentioned before.…”

“…30 Increasing evidence suggests that ERS plays a role in MM, and an appropriate response to ERS may promote tumor growth. 27 However, the potential value of ERGs in MM remains elusive. Therefore, the identification of new biomarkers and investigation of their clinical applicability can offer a fresh diagnostic approach.…”

A highly selective and sensitive endoplasmic reticulum-targeted probe reveals HOCl- and cisplatin-induced H2S biogenesis in live cells

“…Cisplatin is one of the most powerful divalent platinum (Pt II ) anticancer drugs in clinical use, 61 but ER stress is suggested to be the key to the drug-resistance upon cisplatin treatment. 62,63 Considering the effect of H 2 S during cisplatin treatment 64 as well as the ROS-induced H 2 S output, we further envisioned that endogenous H 2 S might be generated during cisplatin-induced ER stress in live cells. To this end, HeLa cells were co-incubated with 10 μM probe 1 and different concentrations (5–20 μM) of cisplatin for 2 h (Fig.…”

“…When cisplatin enters cells, the proteins in ER may not be properly folded and conformed to result in ER stress, 62 which will further induce the over-production of ROS. To alleviate oxidative stress, endogenous H 2 S will be further generated in live cells, providing a supposed mechanism for the cisplatin-induced H 2 S biogenesis (Fig.…”

Antitumoral effects of Bortezomib in malignant mesothelioma: evidence of mild endoplasmic reticulum stress in vitro and activation of T cell response in vivo

“…Our data, obtained using four different MM cell lines, suggest that primary resistance to UPR-mediated apoptosis may as well be an intrinsic common feature of MM cells. Remarkably, these findings have therapeutic implications, since they highlight that the combination with modulators of the UPR, some of which are already clinically available [ 48 , 53 ], may represent a possible strategy to overcome Bor resistance in MM. In this respect, it is also worthy of note that growing evidence points to ER stress signaling as a pharmacological target for MM [ 54 ].…”