Synergistic effect of combined hyperthermia and radiotherapy mediated by AQP5 reduction in pancreatic cancer.

[OBJECTIVE] Pancreatic ductal adenocarcinoma (PDAC), a clinically aggressive stage IV cancer, exhibits poor prognosis and limited therapeutic efficacy due to numerous somatic mutations. In this study, we aimed to elucidate the molecular mechanisms underlying enhanced radiosensitivity in PDAC when hyperthermia was combined with radiotherapy, with a focus on the role of aquaporin 5 (AQP5).

[MATERIALS AND METHODS] Hyperthermia (41 °C-44 °C for 30 min) and radiotherapy (3 Gy) were applied individually or in combination to pancreatic cancer cell lines. AQP5 expression was analyzed by quantitative reverse transcription PCR. Oxidative stress and signaling pathways (ERK, p38 MAPK, and AKT) were evaluated to identify potential underlying mechanisms. To investigate the clinical significance of AQP5, its expression was evaluated by immunohistochemistry in pancreatic cancer tissues across different stages of disease progression.

[RESULTS] Combination treatment significantly reduced AQP5 expression in pancreatic cancer cells compared to monotherapies. This reduction was associated with increased oxidative stress, enhanced apoptosis, and inhibition of ERK/p38 MAPK/AKT signaling pathways. Immunohistochemical analysis revealed elevated AQP5 expression in human PDAC tissues compared to adjacent normal tissues, supporting its clinical relevance.

[CONCLUSIONS] Our findings demonstrate that AQP5 plays a key role in mediating resistance to radiotherapy in PDAC. Its downregulation through combined hyperthermia and radiotherapy enhances radiosensitivity by promoting oxidative stress and blocking survival pathways. AQP5 may serve as a promising molecular target to improve the therapeutic efficacy of combined treatment strategies in pancreatic cancer.