Mechanism of sensitivity to TPF chemoagents and its potential alternative of erbB2 in oral cancer with GDF15 overexpression.

The aim of this study was to: 1) explore the potential mechanism of cancer cell sensitivity to cisplatin, docetaxel, and 5-fluorouracil (TPF) in oral squamous cell carcinoma (OSCC) patients overexpressing growth differentiation factor 15 (GDF15); and 2) identify potential alternative agents for patients who might not benefit from inductive TPF chemotherapy. The results indicated that OSCC cells overexpressing GDF15 were sensitive to docetaxel, cisplatin, and 5-fluorouracil through a caspase-9-dependent pathway both in vitro and in vivo. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential GDF15-binding protein, which was verified by coimmunoprecipitation. GDF15 overexpression promoted OSCC cell proliferation through erbB2 phosphorylation, as well as downstream AKT and Erk signaling pathways. When GDF15 expression was blocked, the phosphorylation of both the erbB2 and AKT/Erk pathways was downregulated. When OSCC cells with GDF15 overexpression were treated with the erbB2 phosphorylation inhibitor, CI-1033, cell proliferation, and xenograft growth colony formation was significantly blocked (P<0.05). Thus, GDF15-overexpressing OSCC tumors are sensitive to TPF chemoagents through caspase-9-dependent pathways. GDF15 overexpression promotes OSCC proliferation via erbB2 phosphorylation. Thus, ErbB2 inhibitors may represent potential targeted drugs or an alternative therapy for OSCC patients with GDF15 overexpression.