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

Corrêa S, Pizzatti L, Du Rocher B, Mencalha A, Pinto D, Abdelhay E - Proteome Sci (2012)

Bottom Line: This resistance has been associated with the emergence of multidrug resistance (MDR) phenotype, as a BCR-ABL independent mechanism.The use of 2-DE coupled with a MS approach resulted in the identification of 36 differentially expressed proteins.In addition, our proteomic approach identified candidate actors involved in resistance, which could lead to additional information on BCR-ABL-independent molecular mechanisms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratório Célula-Tronco, Divisão de Laboratórios do CEMO, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. scorrea@biof.ufrj.br.

ABSTRACT

Background: Although 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.

Results: The 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.

Conclusions: Through 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.

No MeSH data available.


Related in: MedlinePlus

Network analysis of over-expressed proteins involved in resistance. The biological network was generated after the protein's dataset was uploaded into IPA. Gray nodes denote uploaded proteins, and white nodes denote proteins from the IPA database. Lines between the nodes indicate direct protein-protein interactions. Arrowheads show the direction of interaction. Self-regulation is indicated by lines that begin and end on the same node.
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Figure 6: Network analysis of over-expressed proteins involved in resistance. The biological network was generated after the protein's dataset was uploaded into IPA. Gray nodes denote uploaded proteins, and white nodes denote proteins from the IPA database. Lines between the nodes indicate direct protein-protein interactions. Arrowheads show the direction of interaction. Self-regulation is indicated by lines that begin and end on the same node.

Mentions: To better understand resistance biology and to select the most promising candidates for further investigation, we assessed proteins using Ingenuity Pathway Analysis (IPA) (Ingenuity® Systems, http://www.ingenuity.com). We only analyzed direct interactions of increased and decreased proteins (Lucena vs. K562) separately and compared these analyses. The identified proteins were then clustered into two major networks (Figures 5, 6), as well as broader biofunctional groups and canonical pathways, by IPA (Figures 7, 8). The created networks indicated Cellular Function and Maintenance (p = 5.77E-8 - 3.97E-02, 8 molecules); Cell Death (p = 2.86E-06 - 4.55E-02, 14 molecules); DNA Replication, Recombination, and Repair (p = 2.18E-04 - 3.84E-02, 5 molecules); Cell-to-Cell Signaling and Interaction (p = 1.29E-03 - 3.34E-02, 3 molecules) and Small Molecule Biochemistry (p = 1.29E-03 - 3.34E-02, 7 molecules) as the most relevant molecular and cellular functions increased in resistance. Proteins identified by our proteomic approach are shown in gray, and they are sometimes present in more than one biofunctional group. The down-expressed protein dataset did not provide as many statistical results on predominant canonical pathways (Figure 7A) as the up-expressed protein dataset. However, it is known that the Fructose and Mannose Metabolism pathway is down-regulated in the MDR phenotype [21]. Aryl Hydrocarbon Receptor (AHR) Signaling (p = 2.68E-05), Cell Cycle Control of Chromosomal Replication (p = 5.57E-04), Urea Cycle and Metabolism of Amino Groups (p = 7.85E-04), Aldosterone Signaling in Epithelial Cells (p = 9.86E-04) and Mitotic Roles of Polo-Like Kinase (p = 2.83E-03), were the top five canonical pathways represented by the over-expressed proteins in resistant cells. NRF2-mediated Oxidative Stress Response (p = 2.25E-04) and Aryl Hydrocarbon Receptor (AHR) Signaling (p = 4.57E-05) were considered the top pathways in the Toxicity List, also assessed by IPA analysis.


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

Corrêa S, Pizzatti L, Du Rocher B, Mencalha A, Pinto D, Abdelhay E - Proteome Sci (2012)

Network analysis of over-expressed proteins involved in resistance. The biological network was generated after the protein's dataset was uploaded into IPA. Gray nodes denote uploaded proteins, and white nodes denote proteins from the IPA database. Lines between the nodes indicate direct protein-protein interactions. Arrowheads show the direction of interaction. Self-regulation is indicated by lines that begin and end on the same node.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3361502&req=5

Figure 6: Network analysis of over-expressed proteins involved in resistance. The biological network was generated after the protein's dataset was uploaded into IPA. Gray nodes denote uploaded proteins, and white nodes denote proteins from the IPA database. Lines between the nodes indicate direct protein-protein interactions. Arrowheads show the direction of interaction. Self-regulation is indicated by lines that begin and end on the same node.
Mentions: To better understand resistance biology and to select the most promising candidates for further investigation, we assessed proteins using Ingenuity Pathway Analysis (IPA) (Ingenuity® Systems, http://www.ingenuity.com). We only analyzed direct interactions of increased and decreased proteins (Lucena vs. K562) separately and compared these analyses. The identified proteins were then clustered into two major networks (Figures 5, 6), as well as broader biofunctional groups and canonical pathways, by IPA (Figures 7, 8). The created networks indicated Cellular Function and Maintenance (p = 5.77E-8 - 3.97E-02, 8 molecules); Cell Death (p = 2.86E-06 - 4.55E-02, 14 molecules); DNA Replication, Recombination, and Repair (p = 2.18E-04 - 3.84E-02, 5 molecules); Cell-to-Cell Signaling and Interaction (p = 1.29E-03 - 3.34E-02, 3 molecules) and Small Molecule Biochemistry (p = 1.29E-03 - 3.34E-02, 7 molecules) as the most relevant molecular and cellular functions increased in resistance. Proteins identified by our proteomic approach are shown in gray, and they are sometimes present in more than one biofunctional group. The down-expressed protein dataset did not provide as many statistical results on predominant canonical pathways (Figure 7A) as the up-expressed protein dataset. However, it is known that the Fructose and Mannose Metabolism pathway is down-regulated in the MDR phenotype [21]. Aryl Hydrocarbon Receptor (AHR) Signaling (p = 2.68E-05), Cell Cycle Control of Chromosomal Replication (p = 5.57E-04), Urea Cycle and Metabolism of Amino Groups (p = 7.85E-04), Aldosterone Signaling in Epithelial Cells (p = 9.86E-04) and Mitotic Roles of Polo-Like Kinase (p = 2.83E-03), were the top five canonical pathways represented by the over-expressed proteins in resistant cells. NRF2-mediated Oxidative Stress Response (p = 2.25E-04) and Aryl Hydrocarbon Receptor (AHR) Signaling (p = 4.57E-05) were considered the top pathways in the Toxicity List, also assessed by IPA analysis.

Bottom Line: This resistance has been associated with the emergence of multidrug resistance (MDR) phenotype, as a BCR-ABL independent mechanism.The use of 2-DE coupled with a MS approach resulted in the identification of 36 differentially expressed proteins.In addition, our proteomic approach identified candidate actors involved in resistance, which could lead to additional information on BCR-ABL-independent molecular mechanisms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratório Célula-Tronco, Divisão de Laboratórios do CEMO, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. scorrea@biof.ufrj.br.

ABSTRACT

Background: Although 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.

Results: The 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.

Conclusions: Through 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.

No MeSH data available.


Related in: MedlinePlus