Abstract
Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Because of a high rate of immunoglobulin synthesis, the endoplasmic reticulum of MM cells is subjected to elevated basal levels of stress. Consequently, proteasome inhibitors, which exacerbate this stress by inhibiting ubiquitin-proteasome-mediated protein degradation, are an important new class of chemotherapeutic agents being used to combat this disease. However, MM cells still develop resistance to proteasome inhibitors such as carfilzomib. Toward this end, we have established carfilzomib-resistant derivatives of MM cell lines. We found that resistance to carfilzomib was associated with elevated levels of prosurvival autophagy, and Kruppel-like factor 4 (KLF4) was identified as a contributing factor. Expression levels as well as nuclear localization of KLF4 protein were elevated in MM cells with acquired carfilzomib resistance. Chromatin immunoprecipitations indicated that endogenous KLF4 bound to the promoter regions of the SQSTM1 gene encoding the ubiquitin-binding adaptor protein sequestosome/p62 that links the proteasomal and autophagic protein degradation pathways. Ectopic expression of KLF4 induced upregulation of SQSTM1. On the other hand, inhibitors of autophagy sensitized MM cells to carfilzomib, even in carfilzomib-resistant derivatives having increased expression of the multidrug resistance protein P-glycoprotein. Thus, we report here a novel function for KLF4, one of the Yamanaka reprogramming factors, as being a contributor to autophagy gene expression which moderates preclinical proteasome inhibitor efficacy in MM.
Highlights
Multiple myeloma (MM), the second most common hematologic malignancy in the United States, is characterized by the accumulation of clonal plasma cells in the bone marrow [1]
We employed Gene set enrichment analysis (GSEA) to query gene sets in the Molecular Signature Database (MSigDB) to uncover processes or pathways shared between KMS-11/Cfz and KMS-34/Cfz cells that potentially contributed to carfilzomib resistance [14]
In a previously published study, we found that upregulation of the ABCB1-encoded multidrug resistance efflux transporter P-glycoprotein contributed to increased carfilzomib resistance in KMS-34 MM cells cultured in low concentrations (6 nM) of the drug [13]
Summary
Multiple myeloma (MM), the second most common hematologic malignancy in the United States, is characterized by the accumulation of clonal plasma cells in the bone marrow [1]. MM patients initially respond to therapy, they inevitably relapse due to the development of treatment resistance [2]. The introduction of the proteasome inhibitor bortezomib has improved clinical outcome of MM patients [3]. MM cells acquire resistance to bortezomib by diverse mechanisms [4,5,6,7,8]. Carfilzomib is a second generation proteasome inhibitor that was approved in 2012 by the U.S Food and Drug Administration for the treatment of relapsed/refractory MM patients who have received at least two prior therapies including bortezomib and an immunomodulatory drug [9]. It is important to elucidate the underlying mechanisms of proteasome inhibitor resistance in MM and identify novel agents that will enhance therapeutic efficacy of this class of anti-MM drugs
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