Abstract 5468: Expression of aquaporin 11 as a potential predictor of cisplatin sensitivity
Authors: Evans Jason V. , Akhter Anwari , Carbone David P. , Dikov Mikhail M. , Tchekneva Elena E. 
Published: July 2017

Platinum-based combination is a standard of care treatment for lung cancer patients. Accumulating evidence indicates that aquaporins are emerging targets in cancer. Aquaporin 11 (AQP11), a non-ubiquitous member of aquaporins family, is an endoplasmic reticulum (ER)-specific water channel mostly present in epithelial cells and is implicated in the maintenance of ER homeostasis. In our recent publications, we demonstrated that under the stress the reduction of AQP11 expression is a pro-apoptotic factor in normal epithelial cells. We revealed that under normal conditions AQP11 is heavily S-nitrosylated forming functionally important multimeric structures (&gt; 1000 kDa), whereas cisplatin treatment interferes with AQP11 causing its structural and post-translational modification. We hypothesized that if tumor cells express AQP11 then cells with lower levels of AQP11 are not protected from cisplatin-associated ER stress and develop higher sensitivity to drug treatment. In normal lung AQP11 is expressed at low levels. We evaluated the expression of AQP11 in lung cancer cells to determine whether the AQP11 expression correlates with cisplatin sensitivity and whether lower AQP11 expression in lung tumor associates with positive overall survival in patients with lung adenocarcinoma.

A strong link between the level of AQP11 protein expression and cell sensitivity to CP was detected using MTT assay. Screening lung cancer cell lines we found that all tested cancer cell lines expressed AQP11 protein at various levels. Western blot of stress markers showed that cisplatin-treated cells with higher AQP11 expression had lowered cellular and ER stress. Reduction of AQP11 expression using shRNA AQP11 silencing in cispaltin-resistant A549 and HCC827 cell lines, resulted in the significantly increased up to 3-fold sensitivity to cisplatin compared with control shRNA transfected or parental non-transfected cells (p&lt;0.001). In sensitive H460 cells, knocking down AQP11 did not change sensitivity to cisplatin. TCGA database analysis of previously untreated lung adenocarcinoma, detected 13% tumors with elevated AQP11 mRNA expression. Lower AQP11 expression was significantly associated with higher OS and higher median survival rate (52.5 vs. 34.47 mo) than in patients with high AQP11 expression (p&lt;0.05).

AQP11 gene is located within oncogenic 11q13-q14 amplicon, which is a common aberration in solid tumors associated with poor prognosis. The AQP11 is a pro-survival factor protecting tumor cells from cisplatin-induced stress. Low AQP11 expression associates with higher OS in lung adenocarcinoma patients and with higher cispaltin sensitivity in lung cancer cell. The ER stress aggravation via interference with AQP11 could become a prospective therapeutic approach in anti-tumor treatment.

Citation Format: Jason V. Evans, Anwari Akhter, David P. Carbone, Mikhail M. Dikov, Elena E. Tchekneva. Expression of aquaporin 11 as a potential predictor of cisplatin sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2017-5468