A comparative proteomic study identified LRPPRC and MCM7 as putative actors in imatinib mesylate cross-resistance in Lucena cell line

Abstract

BackgroundAlthough chronic myeloid leukemia (CML) treatment has improved since the introduction of imatinib mesylate (IM), cases of resistance have been reported. This resistance has been associated with the emergence of multidrug resistance (MDR) phenotype, as a BCR-ABL independent mechanism. The classic pathway studied in MDR promotion is ATP-binding cassette (ABC) family transporters expression, but other mechanisms that drive drug resistance are largely unknown. To better understand IM therapy relapse due to the rise of MDR, we compared the proteomic profiles of K562 and Lucena (K562/VCR) cells.ResultsThe use of 2-DE coupled with a MS approach resulted in the identification of 36 differentially expressed proteins. Differential mRNA levels of leucine-rich PPR motif-containing (LRPPRC) protein, minichromosome maintenance complex component 7 (MCM7) and ATP-binding cassette sub-family B (MDR/TAP) member 1 (ABCB1) were capable of defining samples from CML patients as responsive or resistant to therapy.ConclusionsThrough the data presented in this work, we show the relevance of MDR to IM therapy. In addition, our proteomic approach identified candidate actors involved in resistance, which could lead to additional information on BCR-ABL-independent molecular mechanisms.

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

“…[31]. In addition to being resistant to daunorubicin and Imatinib [35], MDR cells were shown to express more BCR-ABL kinase and MDR1 than K562 [48], presenting a broad pattern of resistance that includes BCR-ABL independent resistance mechanisms.…”

ABCB1regulation through LRPPRC is influenced by the methylation status of the GC -100 box in its promoter

“…This IM dose was previously reported by our group as the IC 50 for K562 cells, corroborating with literature data. 19 We verified reduced apoptosis induction in K562 cells treated with IM after the 5-Aza-dC treatment (Fig. 6A), compared with K562 cells treated with IM alone.…”

“…Subsequently, we performed a comparative proteomic study to identify proteins that are potentially involved in IM/ MDR-cross resistance in CML, and we reported that LeucineRich protein 130 (LRPPRC) is potentially involved in such resistance. 19 LRPPRC is a member of the pentatricopeptide repeat protein family and is described as a multifunctional protein involved in homeostasis, microtubule alterations, RNA stability, DNA/ RNA binding, transcriptional activity in the mitochondria, metabolic processes, RNA nuclear export and, more recently, in tumorigenesis. [20][21][22][23][24][25][26][27][28][29][30][31][32] Nuclear transcription activity was described in acute lymphoblastic leukemia (ALL) in an MDR cell model.…”

Quantitative- and Phospho-Proteomic Analysis of the Yeast Response to the Tyrosine Kinase Inhibitor Imatinib to Pharmacoproteomics-Guided Drug Line Extension

“…However, and in spite of the drug's established efficacy and generally excellent patient response, primary or acquired resistance is an important clinical issue that frequently leads to a switch of therapy (Apperley, 2007;Karvela et al, 2012;Quintás-Cardama et al, 2009). Resistance mechanisms include several well-characterized processes that implicate the Bcr-Abl kinase, more specifically at the level of point mutations in the kinase domain (Karvela et al, 2012;Quintás-Cardama et al, 2009;Vaidya et al, 2012), but in an estimated 20% of CML cases resistance occurs through Bcr-Abl activity-independent mechanisms (e.g., activation of multidrug resistance pumps), some of which remain uncharacterized (Colavita et al, 2010;Correa et al, 2012;Hentschel et al, 2011;Lee et al, 2007). These mechanisms are of particular relevance in the advanced stages of the disease, when treatment failure is frequently attributed to Bcr-Abl-independent resistance (Eiring et al, 2011;Quintás-Cardama et al, 2009).…”