La Protects Against Cisplatin-Induced Apoptosis in Oropharyngeal SCC Cells

Objective: Chemotherapeutic drugs as cisplatin are an effective agent in treatment of advanced head and neck squamous cell carcinoma (SCC). However, failure of tumors to respond to treatment or tumor recurrence limits the overall success of this therapeutic approach. The RNA-binding protein La is an RNA chaperone known to regulate mRNA translation of a number of cellular proteins. Our published studies demonstrate that the La protein is overexpressed in SCC tissue of oral cavity. 

Method: Reduction of La protein in UM-SCC 22A cells (Dr. T.E. Carey, University of Michigan, USA) was performed by La-specific or control siRNA transfection and overexpression of La protein by transfection of La expression plasmids applying Nucleofector Kit V (Amaxa/Lonza). Apoptosis was determined by FACS analysis applying Annexin-V-FLUOS Staining Kit (Roche). Western blot analysis was performed by applying La-specific antibody 3B9 (a gift from Dr. M. Bachmann, Germany), XIAP-specific antibody (Cell Signaling) and GAPDH-antibody (Santa Cruz Biotechnology) as loading control.

Result: Overexpression of La in oropharyngeal SCC cells correlates with protection against cisplatin-induced apoptosis and increased expression of X-linked inhibitor of apoptosis (XIAP), a well-known inhibitor of programmed cell death (apoptosis). In contrast, siRNA-mediated depletion of La expression sensitizes oropharyngeal SCC cells toward cisplatin-induced apoptosis. 

Conclusion: XIAP is overexpressed in various types of cancer, including oral cancer, and contributes to resistance of tumor cells to cisplatin treatment. Interestingly, it has been shown that La stimulates internal ribosomal entry site (IRES)-dependent translation of XIAP and thereby stimulates its expression. Based on our preliminary data and published studies, we hypothesize that overexpression of the RNA-binding protein La in SCC cells stimulates IRES-dependent XIAP translation and contributes to chemotherapy resistance in oral cancer.