Background: The efficacy of chemotherapeutic treatment of esophageal squamous cell carcinoma (ESCC) is limited by drug resistance during. This severely compromises the long-term survival rate of patients. Therefore, reversing chemotherapy resistance in ESCC may improve the therapeutic outcome. Here, we investigated the molecular mechanism of MUC1-C, the C-terminal transmembrane subunit of MUC1 (a transmembrane heterodimer protein), and its role in the reversal of cisplatin sensitivity in ESCC cells.
Methods: We assessed the efficacy of GO-203, a cell-penetrating peptide, as a chemotherapeutic target of MUC1-C using cell proliferation, colony-forming, and transwell assays. Apoptosis was analyzed in GO-203-treated cells by flow cytometry. Tumor xenograft assay was performed in nude mice to corroborate our in vitro findings.
Results: GO-203 treatment inhibited cell proliferation and restrained the migration and invasion of cisplatin-resistant ESCC. Moreover, targeting MUC1 resulted in enhanced apoptosis in GO-203-treated cells. These in vitro pro-apoptotic and anti-proliferative effects of GO-203 in combination with cisplatin were validated by in vivo models. Significantly smaller tumor volumes were observed in ESCCs-xenografted nude mice treated with GO-203 in combination with cisplatin compared with mice treated with monotherapy or their control counterparts. We found that blocking MUC1-C with GO-203 significantly reversed the cisplatin resistance in ESCC via modulating Akt and ERK pathways.
Conclusions: Our findings suggest that GO-203 may hold potential as an ancillary therapeutic molecule and a chemosensitizer to improve the outcomes of cisplatin-based chemotherapy especially in patients with cisplatin-resistant ESCC.
Keywords: Akt/ERK; Esophageal squamous cell carcinoma (ESCC); GO-203; MUC1-C; cisplatin resistance.
2021 Translational Cancer Research. All rights reserved.