IADR Abstract Archives
Oral Cancer Resistance to Target-Therapy: The Effect of PTEN and c-MET Molecular Interaction
Objectives: Objective: Oral cancer is a complex system composed of tumor cells that have somatic genetic alterations that impacts cancer survival, growth, and response to therapy. HGF and its receptor c-MET are found in most head and neck squamous cell carcinomas (HNSCC) and is known to induce the activation of the PI3K pathway. PTEN is a master regulator of the PI3K pathway and modulates c-MET signaling. PTEN however, is often found downregulated in HNSCC. The objective of this study is to analyse the correlation between compromised PTEN function and c-MET activation in HNSCC tumor response to therapy.
Methods: Methods: We used lentiviral vectors expressing shRNA for PTEN or shRNA control to establish human HNSCC cell lines constitutively presenting PTEN knockdown. Proliferation, migration, and cytokines secretion were analyzed in response to c-MET and PI3K action. Response to c-Met chemotherapy was analyzed using MTT assay. Whole cell lysate was used to identify protein levels of PTEN, phosphor-c-MET, and total c-MET.
Results: Results: Knockdown of PTEN gene was successfully achieved in human HNSCC cell lines using lentiviral vector for shRNA for PTEN compare to shRNA control. The synergism between c-MET signaling and PI3K pathway resulted in increased cellular proliferation and robust secretion of cytokines. Tumor proliferation was particularly found upon HGF treatment in HNSCC cells with PTEN deregulation (±SE, ANOVA, ***p≤0.001). Furthermore, knockdown of PTEN in HNSCC resulted in over two-fold increase of tumor resistance to c-MET inhibitor.
Conclusions: Conclusion: The synergism between c-MET signaling and compromised PTEN functions enhances key tumor biological cues such as proliferation and cytokine secretion by tumor cells and ultimately leads to chemoresistance of HNSCC to c-MET inhibitor.
Methods: Methods: We used lentiviral vectors expressing shRNA for PTEN or shRNA control to establish human HNSCC cell lines constitutively presenting PTEN knockdown. Proliferation, migration, and cytokines secretion were analyzed in response to c-MET and PI3K action. Response to c-Met chemotherapy was analyzed using MTT assay. Whole cell lysate was used to identify protein levels of PTEN, phosphor-c-MET, and total c-MET.
Results: Results: Knockdown of PTEN gene was successfully achieved in human HNSCC cell lines using lentiviral vector for shRNA for PTEN compare to shRNA control. The synergism between c-MET signaling and PI3K pathway resulted in increased cellular proliferation and robust secretion of cytokines. Tumor proliferation was particularly found upon HGF treatment in HNSCC cells with PTEN deregulation (±SE, ANOVA, ***p≤0.001). Furthermore, knockdown of PTEN in HNSCC resulted in over two-fold increase of tumor resistance to c-MET inhibitor.
Conclusions: Conclusion: The synergism between c-MET signaling and compromised PTEN functions enhances key tumor biological cues such as proliferation and cytokine secretion by tumor cells and ultimately leads to chemoresistance of HNSCC to c-MET inhibitor.