XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach
| Autor: | Debasish Paul, Venkatesh Chanukuppa, Khushman Taunk, Manas Kumar Santra, Srikanth Rapole, Tathagata Chatterjee, Sanjeevan Sharma, Saravanan Kumar |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proteomics medicine.medical_treatment Cell Biophysics Receptors Cytoplasmic and Nuclear Soft Agar Assay Antineoplastic Agents Cell Count Karyopherins Biochemistry Flow cytometry Blood cell Bortezomib 03 medical and health sciences Cell Line Tumor medicine Humans Multiple myeloma Chemotherapy 030102 biochemistry & molecular biology medicine.diagnostic_test business.industry Computational Biology medicine.disease Flow Cytometry 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm Gene Knockdown Techniques Proteasome inhibitor Cancer research business Multiple Myeloma medicine.drug |
| Zdroj: | Journal of proteomics. 209 |
| ISSN: | 1876-7737 |
| Popis: | Among the blood cancers, 13% mortality is caused by Multiple myeloma (MM) type of hematological malignancy. In spite of therapeutic advances in chemotherapy treatment, still MM remains an incurable disease is mainly due to emergence of chemoresistance. At present time, FDA approved bortezomib is the first line drug for MM treatment. However, like other chemotherapy, MM patients are acquiring resistance against bortezomib. The present study aims to identify and validate bortezomib resistant protein targets in MM using iTRAQ and label free quantitative proteomic approaches. 112 differentially expressed proteins were commonly found in both approaches with similar differential expression pattern. Exportin-1 (XPO1) protein was selected for further validation as its significant high expression was observed in both iTRAQ and label free analysis. Bioinformatic analysis of these common differentially expressed proteins showed a clear cluster of proteins such as SMC1A, RCC2, CSE1, NUP88, NUP50, TPR, HSPA14, DYNLL1, RAD21 and RANBP2 being associated with XPO1. Functional studies like cell count assay, flow cytometry assay and soft agar assay proved that XPO1 knock down in RPMI 8226R cell line results in re-sensitization to bortezomib drug. The mass spectrometry data are available via ProteomeXchange with identifier PXD013859. BIOLOGICAL SIGNIFICANCE: Multiple myeloma (MM) is a type of hematological malignancy which constitutes about 13% of all blood cell related malignancies. Chemoresistance is one of the major obstacles for the successful treatment for MM. Bortezomib is a first proteasome inhibitor drug, widely used in MM treatment. The present study aims to identify and validate bortezomib resistant protein targets in MM. Here, we identified 112 candidate proteins to be associated with bortezomib resistance using global quantitative proteomic analysis. Among these candidate proteins, we show that XPO1 plays crucial role in emerging bortezomib resistance using functional studies like cell count assay, flow cytometry assay and soft agar assay. XPO1 could be a potential therapeutic target for MM and development of inhibitors of XPO1 might help to cure MM. |
| Databáze: | OpenAIRE |
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