The role of endoplasmic reticulum stress in maintaining and targeting multiple myeloma: a double-edged sword of adaptation and apoptosis

Abstract

Increased cellular protein production places stress on the endoplasmic reticulum (ER), because many of the nascent proteins pass through the ER for folding and trafficking. Accumulation of misfolded proteins in the ER triggers the activation of three well-known pathways including IRE1 (inositol requiring kinase 1), ATF6 (activating transcription factor 6), and PERK (double stranded RNA-activated protein kinase-like ER kinase). The activity of each sensor modulates the overall ER strategy for managing protein quality control as cellular needs change due to growth, differentiation, infection, transformation, and host of other possible physiological states. Here we review the role of ER stress in multiple myeloma (MM), an incurable plasma cell neoplasm. MM is closely linked to dysregulated unfolded protein response in the ER due to the heightened production of immunoglobulin and the metabolic demands of malignant uncontrolled proliferation. Together, these forces may mean that myeloma cells have an “Achilles heel” which can be exploited as a treatment target: their ER stress response must be constitutively active at a remarkably high level to survive their unique metabolic needs. Therefore, inhibition of the ER stress response is likely to injure the cells, as is any further demand on an already over-worked system. Evidence for this vulnerability is summarized here, along with an overview of how each of the three ER stress sensors has been implicated in myeloma pathogenesis and treatment.

One siRNA pool targeting the λ constant region stops λ light-chain production and causes terminal endoplasmic reticulum stress

“…[28][29][30][31] The importance of the PERK-activating transcription factor 4-CHOP arm of the UPR as a potential indicator of caspase-dependent apoptosis highlights a paradoxical aspect of the role of the UPR in plasma cell biology. 32 In this report, knockdown of IgL production and accumulation of unpaired intracellular IgH activate the UPR and ERAD in plasma cells making intact immunoglobulins but not in plasma cells making only IgL. Of note, the loss of IgH production with manufacture of only IgL and the possible toxicity of IgH to plasma cells are fundamental themes in plasma cell biology.…”

Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94

“…Not surprisingly, it was found that gp96 is required for the pathogenesis of myeloma in a mouse model of disease that was driven by overexpression of the spliced variant of X-box binding protein 1 (XBP1s) [115]. Mechanistically, it was shown that gp96 chaperones Wnt signaling co-receptor LRP6, which ensures the long-term survival of myeloma cells by activating downstream target genes including survivin [145]. Thus, the dependence on gp96 to survive might be the ‘Achilles heel’ of myeloma, laying a strong foundation for development of gp96-based inhibitors against this currently incurable disease.…”

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

“…The ER is an organelle that is essential for cell function and survival. Interfering with ER function activates the unfolded protein response (UPR), known as the ER stress response, which is a signal to recover ER function (Ma and Hendershot, 2004;Zhang and Kaufman, 2006;Rasheva and Domingos, 2009;White-Gilbertson et al, 2013). During ER stress, multiple signaling pathways are activated, including double-stranded RNA-activated protein kinase (PKR), the PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2 alpha (eIF2α), which suppress protein synthesis (Prostko et al, 1993;Teske et al, 2011).…”