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Endoplasmic Reticulum Stress in Multiple Myeloma: From Molecular Mechanisms to Therapeutic Opportunities

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Stress Response Pathways in Cancer

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Abstract

The endoplasmic reticulum (ER) is a membrane-bounded intracellular organelle with an essential role in protein synthesis, folding and transport. Accumulation of misfolded proteins in the ER leads to ER stress, which triggers the activation of three well-known pathways including activating inositol requiring kinase 1 (IRE1), the transcription factor activating transcription factor 6 (ATF6), and double stranded RNA-activated protein kinase-like ER kinase (PERK) to induce the expression of several major ER heat shock proteins (HSPs) including gp96, grp78 and calreticulin to enhance protein folding machinery. These signaling pathways are termed unfolded protein response (UPR), which are critical for cell fates. Multiple myeloma (MM) is an incurable plasma cell neoplasm whose pathogenesis is closely linked to dysregulated UPR in ER due to the heightened production of immunoglobulin and the metabolic demands of malignant uncontrolled proliferation. Therefore, inhibition of the ER stress response is likely to injure the MM cells, as is any further demand on an already over-worked system. In this chapter, we discuss the roles of ER stress sensors in plasma cell differentiation and MM pathogenesis. We also summarize the strategies of targeting UPR pathways and HSPs that have been proposed and tested for potential therapeutic benefit against multiple myeloma.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA

    Bei Liu & Zihai Li

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  1. Bei Liu
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  2. Zihai Li
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Correspondence to Bei Liu or Zihai Li .

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  1. Dept. of Pharmacology and Toxicology, Univ. of Arizona, College of Pharm. & The Univ. of Arizona Cancer Ctr., Tucson, Arizona, USA

    Georg T. Wondrak

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Liu, B., Li, Z. (2015). Endoplasmic Reticulum Stress in Multiple Myeloma: From Molecular Mechanisms to Therapeutic Opportunities. In: Wondrak, G. (eds) Stress Response Pathways in Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9421-3_12

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