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Comparative Analysis of Acquired Resistance to Bortezomib in Prostate Cancer Cells Using Proteomic and Bioinformatic
Semih Seker1, Betul Sahin2, Azmi Yerlikaya1
1Department of Medical Biology, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey.
Abstract:
Chemotherapy is a potent tool against cancer, but drug resistance remains a major obstacle. To combat this, understanding the molecular mechanisms behind resistance in cancer cells and the protein expression changes driving these mechanisms is crucial. Targeting the Ubiquitin-Proteasome System (UPS) has proven effective in treating multiple myeloma and shows promise for solid tumours. Despite initial success with the proteasome inhibitor bortezomib, acquired resistance soon after treatment poses a significant challenge to its efficacy. In this study, we explored proteins potentially involved in acquired resistance to bortezomib using label-free nLC-MS/MS proteomic analysis. The investigation revealed 299 proteins with notable differences in expression levels in the bortezomib-resistant PC3 prostate cancer cell line. Using bioinformatics tools, we illustrated the top 10 gene ontology (GO) processes [e.g., translational initiation (p = 5.964E-10), CRD-mediated mRNA stabilisation (p = 1.636E-5), and hydrogen ion transmembrane transport (p = 6.46E-5)] and the top 20 KEGG [e.g., metabolic pathways (p = 7.601E-13), biosynthesis of amino acids (p = 3.834E-12), and chemical carcinogenesis-reactive oxygen species (p = 1.891E-4)] and REACTOME [e.g., metabolism (p = 4.182E-21), translation (p = 9.484E-18), and Nonsense-Mediated Decay (NMD) (p = 1.829E-8)] pathways in the PC3-resistant cells. We further refined our results by comparing them with globally validated TCGA datasets. We correlated the 299 proteins identified through proteomic analysis with tumour aggressiveness and resistance by comparing them with the TCGA nodal metastasis N0 vs. N1 datasets using the UALCAN portal and identified 37 proteins consistent with our results. We believe that a combination of bortezomib with chemotherapeutics targeting these proteins could be effective in overcoming the resistance developed against bortezomib.
Insights
Understanding bortezomib resistance in prostate cancer is key. This study identified 299 proteins and 37 key targets in resistant cells, offering new strategies to overcome chemotherapy resistance.
Area of Science:
- Proteomics and Bioinformatics in Cancer Research
- Molecular Mechanisms of Drug Resistance
Background:
- Chemotherapy is vital for cancer treatment, but drug resistance, particularly to proteasome inhibitors like bortezomib, hinders efficacy.
- The Ubiquitin-Proteasome System (UPS) is a validated therapeutic target, showing promise in multiple myeloma and solid tumors.
- Acquired resistance to bortezomib necessitates understanding the underlying molecular changes in cancer cells.
Purpose of the Study:
- To identify proteins associated with acquired bortezomib resistance in PC3 prostate cancer cells.
- To elucidate the molecular pathways and biological processes involved in bortezomib resistance.
- To correlate proteomic findings with clinical data for potential therapeutic targets.
Main Methods:
- Label-free nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) proteomic analysis of bortezomib-resistant PC3 cells.
- Bioinformatic analysis of Gene Ontology (GO), KEGG, and REACTOME pathways.
- Correlation of identified proteins with The Cancer Genome Atlas (TCGA) datasets (nodal metastasis N0 vs. N1) using the UALCAN portal.
Main Results:
- Identified 299 proteins with differential expression in bortezomib-resistant PC3 cells.
- Bioinformatic analysis highlighted key affected pathways including translational initiation, mRNA stabilization, metabolic pathways, and Nonsense-Mediated Decay (NMD).
- Cross-referencing with TCGA data identified 37 proteins consistently associated with tumor aggressiveness and resistance.
Conclusions:
- The study reveals significant proteomic alterations contributing to bortezomib resistance in prostate cancer.
- Identified proteins and pathways provide potential targets for overcoming bortezomib resistance.
- Combination therapies targeting these identified proteins alongside bortezomib may enhance treatment efficacy.
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