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Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach
Huiming Peng1, Tao Peng1, Jianguo Wen1
1Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
Motivation:
p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown.
Method:
To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph.
Results:
New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection.
Availability And Implementation:
RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php.
Insights
p38 isoforms regulate drug resistance in multiple myeloma (MM) by impacting ERK and NFκB pathways. Targeting these pathways with novel drug combinations may overcome resistance, offering new therapeutic strategies for MM patients.
Area of Science:
- Biochemistry
- Systems Biology
- Oncology
Background:
- p38 mitogen-activated protein kinase (MAPK) activation is crucial in chemotherapeutic drug resistance in multiple myeloma (MM).
- The specific roles of different p38 isoforms in mediating this drug resistance remain largely unelucidated.
Purpose of the Study:
- To investigate the mechanisms by which p38 MAPK signaling pathways contribute to drug resistance in MM.
- To identify the distinct roles of p38 isoforms in regulating key cellular pathways involved in MM drug resistance.
Main Methods:
- A novel systems biology approach integrating liquid chromatography-mass spectrometry (LC-MS) and reverse phase protein array (RPPA) data.
- Computational pathway modeling with parameter inference using a modularized factor graph algorithm.
Main Results:
- Models predicted that combined p38 isoform activation contributes to MM drug resistance by regulating extracellular signal-regulated kinase (ERK) and nuclear factor kappa B (NFκB) pathways.
- The p38δ isoform was found to synergistically regulate the ERK pathway (cell growth), while the p38α isoform synergistically regulated the NFκB pathway (apoptosis).
- Experimental validation confirmed p38δ isoform promotes ERK1/2 phosphorylation in bortezomib-treated MM cells; in silico drug screening identified promising combination therapies targeting ERK1/2 and NFκB.
Conclusions:
- This study elucidates novel mechanisms of p38 isoform-mediated drug resistance in MM.
- A systems biology framework was established for studying drug resistance and optimizing drug combination selection.
- Targeting both ERK and NFκB pathways presents a potential strategy to overcome drug resistance in MM.
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