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Updated: Jun 17, 2025
Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Activity-based protein profiling and global proteome analysis reveal MASTL as a potential therapeutic target in
Kyoung-Min Choi1, Sung-Jin Kim1, Mi-Jung Ji2
1Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.
Background:
Gastric cancer (GC) is a prevalent malignancy with limited therapeutic options for advanced stages. This study aimed to identify novel therapeutic targets for GC by profiling HSP90 client kinases.
Methods:
We used mass spectrometry-based activity-based protein profiling (ABPP) with a desthiobiotin-ATP probe, combined with sensitivity analysis of HSP90 inhibitors, to profile kinases in a panel of GC cell lines. We identified kinases regulated by HSP90 in inhibitor-sensitive cells and investigated the impact of MASTL knockdown on GC cell behavior. Global proteomic analysis following MASTL knockdown was performed, and bioinformatics tools were used to analyze the resulting data.
Results:
Four kinases-MASTL, STK11, CHEK1, and MET-were identified as HSP90-regulated in HSP90 inhibitor-sensitive cells. Among these, microtubule-associated serine/threonine kinase-like (MASTL) was upregulated in GC and associated with poor prognosis. MASTL knockdown decreased migration, invasion, and proliferation of GC cells. Global proteomic profiling following MASTL knockdown revealed NEDD4-1 as a potential downstream mediator of MASTL in GC progression. NEDD4-1 was also upregulated in GC and associated with poor prognosis. Similar to MASTL inhibition, NEDD4-1 knockdown suppressed migration, invasion, and proliferation of GC cells.
Conclusions:
Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.
Insights
Targeting microtubule-associated serine/threonine kinase-like (MASTL) shows promise for advanced gastric cancer (GC). Inhibiting MASTL or its downstream mediator NEDD4-1 reduces GC cell migration, invasion, and proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Gastric cancer (GC) presents limited treatment options for advanced stages.
- Identifying novel therapeutic targets is crucial for improving GC patient outcomes.
- Heat shock protein 90 (HSP90) client kinases are potential targets for cancer therapy.
Purpose of the Study:
- To identify novel therapeutic targets for gastric cancer by profiling HSP90 client kinases.
- To investigate the role of identified kinases in GC progression.
- To explore potential therapeutic strategies targeting identified kinases.
Main Methods:
- Activity-based protein profiling (ABPP) using mass spectrometry to profile kinases in GC cell lines.
- Sensitivity analysis of HSP90 inhibitors to identify regulated kinases.
- Investigating the impact of microtubule-associated serine/threonine kinase-like (MASTL) knockdown on GC cell behavior and global proteomic changes.
Main Results:
- Four kinases (MASTL, STK11, CHEK1, MET) were identified as HSP90-regulated.
- MASTL was upregulated in GC, associated with poor prognosis, and its knockdown reduced GC cell migration, invasion, and proliferation.
- NEDD4-1 was identified as a downstream mediator of MASTL, also upregulated in GC, and its knockdown suppressed GC cell progression.
Conclusions:
- Targeting MASTL represents a promising therapeutic strategy for advanced gastric cancer.
- MASTL inhibition may exert its anti-tumor effects by reducing NEDD4-1 levels.
- This study provides new insights into kinase signaling in GC and potential treatment avenues.
