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Updated: Mar 2, 2026

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential
Bharath K Velmurugan1, Chien-Hung Lee2,3, Shang-Lun Chiang4,5
1Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
Abstract:
Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3-stage (aOR = 2.1, 95%CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR = 2.2, 95%CI: 1.2-4.0) and lower 10-year overall survival (p = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated in oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC.
Insights
Protein phosphatase 2A (PP2A) deactivation, marked by tyrosine-307 hyperphosphorylation, is common in oral cancer. Restoring PP2A with FTY720 may offer a therapeutic strategy for oral squamous cell carcinoma (OSCC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Protein phosphatase 2A (PP2A) acts as a tumor suppressor, frequently deactivated in various cancers.
- The specific role and clinical significance of PP2A in oral squamous cell carcinoma (OSCC) are not well-established.
Purpose of the Study:
- To investigate the deactivation mechanisms of PP2A in oral cancer.
- To evaluate the clinical relevance of PP2A phosphorylation in OSCC patient outcomes.
- To explore FTY720 as a potential therapeutic agent for OSCC.
Main Methods:
- Assessed PP2A deactivation in oral cancer cells, focusing on tyrosine-307 (Y307) phosphorylation.
- Treated cells with FTY720 to restore PP2A activity and monitored cell growth and downstream signaling (GSK-3β phosphorylation).
- Analyzed PP2A phosphorylation levels in 262 OSCC tissue samples and correlated findings with clinical staging and patient survival.
Main Results:
- PP2A deactivation via Y307 hyperphosphorylation is prevalent in oral cancer cells.
- FTY720 treatment reactivated PP2A, inhibited cell growth, and reduced GSK-3β phosphorylation.
- Elevated p-PP2A expression in tumors correlated with advanced N2/N3 stage and poorer overall survival, particularly in cases with lymph node metastasis.
- High p-PP2A expression was a significant predictor of mortality density and reduced 10-year survival.
Conclusions:
- PP2A deactivation is a frequent event in oral cancer, linked to poor prognosis.
- Restoring PP2A function using FTY720 presents a potential therapeutic avenue for OSCC treatment.
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