Proteomics study of MG-63 drug- resistance cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Suwei Dong
PROVIDER: PXD059020 | iProX | Thu Dec 19 00:00:00 GMT 2024
REPOSITORIES: iProX
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Project description:Due to the lack of a precise in vitro model that can mimic the nature microenvironment in osteosarcoma, the understanding of its resistance to chemical drugs remains limited. Here, we report a novel three-dimensional model of osteosarcoma constructed by seeding tumor cells (MG-63 and MNNG/HOS Cl #5) within in demineralized bone matrix scaffolds. Demineralized bone matrix scaffolds retain the original components of the natural bone matrix (hydroxyapatite and collagen type I), and possess good biocompatibility allowing osteosarcoma cells to proliferate and aggregate into clusters within the pores. Growing within the scaffold conferred elevated resistance to doxorubicin on MG-63 and MNNG/HOS Cl #5 cell lines as compared with two-dimensional cultures. Transcriptomic analysis showed an increased enrichment for drug resistance genes along with enhanced glutamine metabolism in osteosarcoma cells in demineralized bone matrix scaffolds. Inhibition of glutamine metabolism resulted a decrease in drug resistance of osteosarcoma, which could be restored by α-ketoglutarate supplementation. Overall, our study suggests that microenvironmental cues in demineralized bone matrix scaffolds can enhance osteosarcoma drug responses and that targeting glutamine metabolism may be a strategy for treating osteosarcoma drug resistance.
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Proteome analysis confirmed the presence of the Senescence-Associated Secretory Phenotype (SASP), altered spliceosomal activity and proteins with significant role in immune evasion.
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Project description:Palbociclib is a specific CDK4/6 inhibitor that has been widely applied in multiple tumor types. Different from cytotoxic drugs, the anticancer mechanism of palbociclib mainly depends on cell cycle inhibition. Therefore, the resistance mechanism is different. For clinical cancer patients, drug resistance is inevitable for almost all cancer therapies including palbociclib. We have trained palbociclib resistance cell lines in vitro to monitor the clinical situation and applied LC-MS-based proteomic and glycoproteomic technology to deeply understand the underly mechanism behind the resistance. As a result, the resistant cells mainly relied on an alternative metabolic pathway to keep proliferation based on proteomic analysis. Metabolic processes related to carbohydrates, lipids, DNA, cellular proteins, glucose, and amino acids were observed to be upregulated. Most dramatically, the protein expression of COX-1 and NDUFB8 have been detected to be significantly overexpressed. When a COX-1 inhibitor was hired to combine with palbociclib, a synergistic effect could be obtained, suggesting the altered COX-1 involved metabolic pathway is the major reason for the acquired palbociclib resistance. Additionally, through glycoproteomic analysis, the global glycosylation was found to be elevated in the palbociclib-resistant cells. Moreover, the integration of glycoproteomic data allowed us to detect a lot more proteins that have been glycosylated with low abundance, these proteins were normally overwhelmed by those highly abundant proteins during regular proteomic LC-MS detection. These low abundant glycoproteins are mainly involved in the cellular biology process of cell migration, regulation of chemotaxis, as well as glycoprotein metabolic process which offered us a great more detail on the roles the alternated glycan modification played during drug resistance. The high efficiency of the integrated proteomic and N-glycoproteomic workflow in discovering drug resistance mechanisms paves the new way for drug development. With a clear understanding of the resistance mechanism, new drug targets and drug combinations could be designed to resensitize the resistant tumors.
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