AQP9-induced cell cycle arrest is associated with RAS activation and improves chemotherapy treatment efficacy in colorectal cancer

Abstract

Aquaporin-9 (AQP9) expression is associated with arsenic sensitivity in leukemia cells. However, the role of AQP9 in regulating tumor sensitivity to adjuvant chemotherapy in colorectal cancer (CRC) has not been elucidated. In this study, we demonstrated that AQP9 can serve as an independent predictive marker for adjuvant chemotherapy in CRC. Patients with high AQP9 expression had higher rate of disease-free survival (DFS) than those with low AQP9 expression. Upregulation of AQP9 was associated with enhanced chemosensitivity to 5-fluorouracil (5-FU) both in vitro and in vivo. Overexpression of AQP9 resulted in an increased intracellular level of 5-FU in CRC cells, hence leading to a higher percentage of apoptosis after 5-FU treatment. Moreover, AQP9 is positively associated with RAS activation and other downstream signaling molecules in CRC. AQP9 overexpression resulted in p21 upregulation and induced S-phase arrest. Taken together, AQP9 enhances the cytotoxic response to 5-FU in CRC cells by simultaneously inducing S-phase arrest via activation of RAS signaling and facilitating drug uptake. Our results suggest that AQP9 might be a novel predictor for the benefit of 5-FU-based chemotherapy in CRC. The identification of AQP9-induced tumor sensitivity to 5-FU highlights the role of AQP9 in regulating chemosensitivity in CRC.

Ectopic expression of aquaporin-5 in noncancerous epithelial MDCK cells changes cellular morphology and actin fiber formation without inducing epithelial-to-mesenchymal transition

“…This was also demonstrated for AQP9, as inward water fluxes weakened membranecytoskeleton anchorage and increased filopodia formation (15,20). Interestingly, despite these functional properties of AQP9, which would suggest an oncogenic effect, AQP9 expression has been found to suppress cancer cell progression (10,18,50). In this study we found that AQP5-expressing MDCK cells displayed unchanged filopodia formation but more dynamic lamellipodia compared with control cells.…”

“…These studies showed that AQP9 expression stimulated cellular filopodia and protrusion formation, structures that enable cell migration. Surprisingly, in contrast to cancer cells expressing AQP5, overexpression of AQP9 in cancer cells decreased EMT and improved cancer treatment (10,18,50).…”

Significance of aquaporins’ expression in the prognosis of gastric cancer

“…Huang et al [ 37 ] showed that high expression of AQP9 was correlated with improved disease-free survival (DFS) and increased chemosensitivity in stage III colorectal cancer. Nonetheless, AQP9 mRNA expression and its role in gastric cancer remains to be clarified along with tumor marker and suppression characteristics.…”

Prognostic values of aquaporins mRNA expression in human ovarian cancer

“…Our results showed that high expression of AQP2 mRNA had no effect on the prognosis of all ovarian cancer patients, serous ovarian cancer patients, as well as in endometrioid ovarian cancer patients. As for AQP9, Huang et al [ 24 ] reported that AQP9 could serve as an independent predictive biomarker for adjuvant chemotherapy, and they demonstrated that high AQP9 expression was related to better disease-free survival in colorectal cancer patients treated with chemotherapy. However, the study of Tan et al [ 25 ] indicated that the expression of both AQP9 mRNA and protein was significantly up-regulated in astrocytic tumors and was positively associated with pathological grade, suggesting that AQP9 might play a critical role in the malignant progression of brain astrocytic tumors.…”