Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-κB activity

Abstract

BackgroundThe addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line.MethodsEffects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses.ResultsGene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-κB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment, indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance. The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment.ConclusionWe show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-κB are the main molecular events driving cytarabine resistance development.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4346-1) contains supplementary material, which is available to authorized users.

Proteasome Inhibitors Interrupt the Activation of Non-Canonical NF-κB Signaling Pathway and Induce Cell Apoptosis in Cytarabine-Resistant HL60 Cells

“…Exogenous Cyr61 effectively reduces cytarabine-induced apoptosis through the NF-κB signaling pathway in acute lymphoblastic leukemia cells [ 22 ]. Upregulation of NF-κB is the main molecular process driving the development of cytarabine resistance in Z138 cells [ 23 ]. Cripto-1, an oncoprotein, promotes resistance to cytarabine-induced apoptosis by activating the TAK-1/NF-κB/survivin signaling pathway [ 24 ].…”

A gene expression signature‐based nomogram model in prediction of breast cancer bone metastases

“…It has been found that REEP1 could facilitate mitochondrial‐ER interactions, which may result in intracellular Ca 2+ overload and axonal damage, and REEP1 variants were recognized as causes of Neurological Disease like hereditary spastic paraplegia (HSP) and distal hereditary motor neuropathy (dHMN) . The third gene SPIB, encoding an ETS‐domain transcription factor, was believed to be associated with cancers especially in lymphomas . Also, Yi‐Jung et al found the SPIB may be involved in tumorigenesis in live cancer, and Wei et al reported that SPIB is expressed in invasive cancer cells in human primary lung cancer tissues.…”

“…37 The third gene SPIB, encoding an ETS-domain transcription factor, was believed to be associated with cancers especially in lymphomas. 38,39 Also, Yi-Jung et al 40 found the SPIB may be involved in tumorigenesis in live cancer, and Wei et al 41 reported that SPIB is expressed in invasive cancer cells in human primary lung cancer tissues. ALDH3B2 was widely known as a member of aldehyde dehydrogenases (ALDHs).…”

Drug Resistance in Non-Hodgkin Lymphomas

“…In analogy, the downregulation of DCK observed in MCL cells with acquired resistance to fludarabine was associated with "cross"-resistance to ara-C, gemcitabine, and cladribine [118]. Freiburghaus et al recently confirmed that the downregulation of DCK belongs to key molecular events responsible for ara-C resistance and reported that it can be prevented by treatment with the proteasome inhibitor bortezomib [119]. The downregulation of SLC29A1/hENT1 ara-C transporter and upregulation of cytidine-deaminase (that inactivates ara-C to an inactive metabolite) were detected in ara-C-resistant AML cells [65,66].…”