Abstract
Although targeting radioresistant tumor cells is essential for enhancing the efficacy of radiotherapy, the signals activated in resistant tumors are still unclear. This study shows that ERp57 contributes to radioresistance of laryngeal cancer by activating STAT3. Increased ERp57 was associated with the radioresistant phenotype of laryngeal cancer cells. Interestingly, increased interaction between ERp57 and STAT3 was observed in radioresistant cells, compared to the control cells. This physical complex is required for the activation of STAT3 in the radioresistant cells. Among STAT3-regulatory genes, Mcl-1 was predominantly regulated by ERp57. Inhibition of STAT3 activity with a chemical inhibitor or siRNA-mediated depletion of Mcl-1 sensitized radioresistant cells to irradiation, suggesting that the ERp57-STAT3-Mcl-1 axis regulates radioresistance of laryngeal cancer cells. Furthermore, we observed a positive correlation between ERp57 and phosphorylated STAT3 or Mcl-1 and in vivo interactions between ERp57 and STAT3 in human laryngeal cancer. Importantly, we also found that increased ERp57-STAT3 complex was associated with poor prognosis in human laryngeal cancer, indicating the prognostic role of ERp57-STAT3 regulation. Overall, our data suggest that ERp57-STAT3 regulation functions in radioresistance of laryngeal cancer, and targeting the ERp57-STAT3 pathway might be important for enhancing the efficacy of radiotherapy in human laryngeal cancer.
Highlights
Radiotherapy is the standard treatment modality for localized laryngeal cancer, which is the largest subgroup of head and neck cancer
ERp57 did not translocate to the plasma membrane in response to irradiation (Fig. 1C), whereas ERp57 was detected in the nuclei of RR-HEp-2 cells but not in the nuclei of control cells (Fig. 1C and D), implying that the nuclear function of ERp57 is associated with the radioresistance
We demonstrated that ERp57 modulated radioresistance of laryngeal cancer cells by directly activating STAT3 and, in turn, triggered increased Mcl-1 expression, thereby contributing to tumor radioresistance of laryngeal cancer cells
Summary
Radiotherapy is the standard treatment modality for localized laryngeal cancer, which is the largest subgroup of head and neck cancer. Radiotherapy is generally preferred in patients with laryngeal cancer because it allows for better organ preservation [1, 2]. Despite progress in the delivery of the ionizing radiation doses over the past 2–3 decades, many patients still suffer from local recurrence after radiotherapy [3, 4]. Drugs that inhibit the molecular targets contributing to the radioresistance of tumor cells will be essential to improve radiotherapy. Several molecular targets modulating tumor survival and the microenvironment have been shown to influence the outcome of radiotherapy [5], clinically relevant targets and www.impactjournals.com/oncotarget signaling pathways are still unclear.
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