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Proteomic Level Changes on Treatment in MCF-7/DDP Breast Cancer Drug- Resistant Cells
Gongshen Jin1, Kangwei Wang1, Yonghong Liu2
1Department of Surgical Oncology, The First Affiliated Hospital of Bengbu, Medical University, 287 Changhuai Road, Bengbu, Anhui 233030, China.
Background:
LCL161, a SMAC'S small molecule mimetic, can bind to a variety of IAPs and activate Caspases. We found that on its own, LCL161induces apoptosis of drug-resistant breast cancer cells by binding to a variety of IAPs and activating Caspases. However, when LCL161 is used in combination with Caspase Inhibitors (CI), its capacity to induce apoptosis of breast cancer cells is enhanced.
Objective:
To carry out proteomic and bioinformatics analysis of LCL161 in combination with CI. We aim to identify the key proteins and mechanisms of breast cancer drug-resistant apoptosis, thereby aiding in the breast cancer drug resistance treatment and identification of drug targeting markers.
Methods:
Cell culture experiments were carried out to explore the effect of LCL161 combined with CI on the proliferation of breast cancer drug-resistant cells. Proteomic analysis was carried out to determine the protein expression differences between breast cancer drug-resistant cells and LCL161 combined with CI treated cells. Bioinformatics analysis was carried out to determine its mechanism of action. Validation of proteomics results was done using Parallel Reaction Monitoring (PRM).
Results:
Cell culture experiments showed that LCL161 in combination with CI can significantly promote the apoptosis of breast cancer drug-resistant cells. Up-regulation of 92 proteins and down-regulation of 114 proteins protein were noted, of which 4 were selected for further validation.
Conclusion:
Our results show that LCL161 combined with CI can promote the apoptosis of drug-resistant breast cancer cells by down-regulation of RRM2, CDK4, and ITGB1 expression through Cancer pathways, p53 or PI3K-AKT signaling pathway. In addition, the expression of CDK4, RRM2, and CDC20 can be down-regulated by the nuclear receptor pathway to affect DNA transcription and replication, thereby promoting apoptosis of breast cancer drug-resistant cells.
Insights
LCL161 combined with Caspase Inhibitors (CI) enhances apoptosis in drug-resistant breast cancer cells. This combination targets key proteins involved in cell survival pathways, offering new therapeutic strategies for breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- LCL161, a small molecule mimetic of SMAC, targets Inhibitor of Apoptosis Proteins (IAPs) to activate Caspases.
- LCL161 alone induces apoptosis in drug-resistant breast cancer cells.
- Combining LCL161 with Caspase Inhibitors (CI) potentiates its apoptotic effect on breast cancer cells.
Purpose of the Study:
- To elucidate the proteomic and bioinformatics mechanisms underlying the synergistic apoptosis induced by LCL161 and CI in drug-resistant breast cancer.
- To identify key proteins and pathways involved in overcoming drug resistance.
- To discover potential therapeutic targets for breast cancer treatment.
Main Methods:
- Cell culture experiments to assess the impact of LCL161 + CI on cell proliferation and apoptosis.
- Proteomic analysis to identify differential protein expression.
- Bioinformatics analysis to determine the mechanism of action.
- Parallel Reaction Monitoring (PRM) for validation of proteomic findings.
Main Results:
- LCL161 + CI significantly promoted apoptosis in drug-resistant breast cancer cells.
- Proteomic analysis revealed up-regulation of 92 proteins and down-regulation of 114 proteins.
- Four key proteins were selected for further validation.
Conclusions:
- LCL161 + CI promotes apoptosis by down-regulating RRM2, CDK4, and ITGB1 via Cancer, p53, or PI3K-AKT signaling pathways.
- The combination therapy also affects DNA transcription and replication through the nuclear receptor pathway by down-regulating CDK4, RRM2, and CDC20.
- This study provides insights into overcoming breast cancer drug resistance and identifies potential therapeutic targets.
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