Aquaporin-3 and Aquaporin-5 Facilitate Migration and Cell–Cell Adhesion in Pancreatic Cancer by Modulating Cell Biomechanical Properties

Abstract

Background: Aquaporins are membrane channels responsible for the bidirectional transfer of water and small non-charged solutes across cell membranes. AQP3 and AQP5 are overexpressed in pancreatic ductal adenocarcinoma, playing key roles in cell migration, proliferation, and invasion. Here, we evaluated AQP3 and AQP5 involvement in cell biomechanical properties, cell–cell adhesion, and cell migration, following a loss-of-function strategy on BxPC-3 cells. Results: Silencing of AQP3 and AQP5 was functionally validated by reduced membrane permeability and had implications on cell migration, slowing wound recovery. Moreover, silenced AQP5 and AQP3/5 cells showed higher membrane fluidity. Biomechanical and morphological changes were assessed by atomic force microscopy (AFM), revealing AQP5 and AQP3/5 silenced cells with a lower stiffness than their control. Through cell–cell adhesion measurements, the work (energy) necessary to detach two cells was found to be lower for AQP-silenced cells than control, showing that these AQPs have implications on cell–cell adhesion. Conclusion: These findings highlight AQP3 and AQP5 involvement in the biophysical properties of cell membranes, whole cell biomechanical properties, and cell–cell adhesion, thus having potential implication in the settings of tumor development.

Aquaporins Transcripts with Potential Prognostic Value in Pancreatic Cancer

“…It is worth mentioning that several studies have revealed AQP3’s association with cancer aggressiveness and invasiveness in diverse types of cancer. In fact, AQP3 has been reported as a crucial player in cell migration and invasion in breast cancer, cell migration and adhesion in pancreatic cancer, and invasiveness in prostate cancer [ 13 , 35 , 36 , 37 ]. Interestingly, through a large-scale proteomic analysis, AQP3 was found to be significantly associated with the activity of mTOR signaling [ 38 ].…”

“…The 13 AQPs found in humans (AQP0–AQP12) have been detected not only in tissues involved in fluid transport but also in non-absorbing or non-excretory tissues [ 11 ]. In addition to acting as membrane channels, AQPs have multiple functions beyond their canonic role; they facilitate cell morphology changes [ 12 ], modulate membranes’ biomechanical properties [ 13 ], and are involved in signaling pathways controlling cell migration and cell–cell adhesion [ 14 , 15 , 16 , 17 ], therefore impacting the initiation and development of carcinogenesis.…”

Unraveling the Aquaporin-3 Inhibitory Effect of Rottlerin by Experimental and Computational Approaches

“…Aquaporins have been associated with cancer invasion, and metastasis [ 25 ] and, in particular, AQP3 seems to affect cellular functions commonly associated with cancer progression, including proliferation, migration and metastasis [ 19 , 29 , 30 , 47 , 48 ]. The current study reveals for the first time the ability of RoT to inhibit AQP3 activity, an aquaporin with a key role in tumor growth and spread by mechanisms still under investigation.…”

AQP3-Dependent PI3K/Akt Modulation in Breast Cancer Cells

“…Therefore, we further investigated the correlation of AQP3 with the PI3K/Akt pathway which was reported as dysregulated in cancer. Previously, we showed that AQP3 has the ability to channel H2O2 to into the pa atic cell line BxPC-3 [22,23]. Therefore, to assess if lipid raft disruption and EGF trea affect peroxiporin activity, we evaluated H2O2 membrane permeability by measurin rate of ROS accumulation due to H2O2 influx in breast cancer cells.…”