Clarifying the molecular mechanism associated with carfilzomib resistance in human multiple myeloma using microarray gene expression profile and genetic interaction network

Abstract

Carfilzomib is a Food and Drug Administration-approved selective proteasome inhibitor for patients with multiple myeloma (MM). However, recent studies indicate that MM cells still develop resistance to carfilzomib, and the molecular mechanisms associated with carfilzomib resistance have not been studied in detail. In this study, to better understand its potential resistant effect and its underlying mechanisms in MM, microarray gene expression profile associated with carfilzomib-resistant KMS-11 and its parental cell line was downloaded from Gene Expression Omnibus database. Raw fluorescent signals were normalized and differently expressed genes were identified using Significance Analysis of Microarrays method. Genetic interaction network was expanded using String, a biomolecular interaction network JAVA platform. Meanwhile, molecular function, biological process and signaling pathway enrichment analysis were performed based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Totally, 27 upregulated and 36 downregulated genes were identified and a genetic interaction network associated with the resistant effect was expanded basing on String, which consisted of 100 nodes and 249 edges. In addition, signaling pathway enrichment analysis indicated that cytokine–cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways were aberrant in carfilzomib-resistant KMS-11 cells. Thus, in this study, we demonstrated that carfilzomib potentially conferred drug resistance to KMS-11 cells by cytokine–cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways, which may provide some potential molecular therapeutic targets for drug combination therapy against carfilzomib resistance.

Keywords:

• multiple myeloma
• carfilzomib
• drug resistance
• microarray
• interaction network
• compensate pathways

Acknowledgments

We would like to thank Gene Expression Omnibus (GEO), Significance Analysis of Microarrays (SAM), Database for Annotation, Visualization and Integrated Discovery and String databases for making their data readily available to the scientific community.

This work was supported by the National Natural Science Foundation of China (No 81141052). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Authors contribution

All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.