PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential

• Published in: Journal of cellular physiology Vol. 233; no. 2; pp. 1300 - 1311
• Main Authors: Velmurugan, Bharath K., Lee, Chien‐Hung, Chiang, Shang‐Lun, Hua, Chun‐Hung, Chen, Mei‐Chung, Lin, Shu‐Hui, Yeh, Kun‐Tu, Ko, Ying‐Chin
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2018
• Subjects: Activation; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - pharmacology; Calyculin‐A; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Deactivation; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators - pharmacology; Female; Fingolimod Hydrochloride - pharmacology; FTY720; Glycogen Synthase Kinase 3 beta - metabolism; GSK‐3β; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Humans; Kaplan-Meier Estimate; Logistic Models; Lymph; Lymph nodes; Lymphatic system; lymphnode metastasis; Male; Metastases; Metastasis; Middle Aged; Mouth Neoplasms - drug therapy; Mouth Neoplasms - enzymology; Mouth Neoplasms - mortality; Mouth Neoplasms - pathology; Multivariate Analysis; Neoplasm Staging; Odds Ratio; Oral cancer; Oral squamous cell carcinoma; OSCC; Phosphatase; Phosphoprotein phosphatase; Phosphorylation; PP2A; Proportional Hazards Models; Protein phosphatase; Protein Phosphatase 2 - metabolism; Restoration; Risk Factors; Signal Transduction - drug effects; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Survival; Target detection; Time Factors; Tumor suppressor genes; Tyrosine; GSK-3β; OSCC; PP2A; lymphnode metastasis; Calyculin-A; FTY720
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.26001

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. 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. 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.