The bowl-shaped structure of PIEZO channels is predicted to flatten in response to mechanical stimuli, gating their pore open. However, how this unique structure allows them to detect exquisitely small changes in membrane tension remains unclear. Here, using pressure clamp electrophysiology, modeling, and molecular dynamics simulations, we show that the single channel open probability of PIEZO1 increases weakly with respect to pressure-induced tension. In contrast, when multiple channels are present in a membrane patch, channel open probability increases steeply as a function of the number of open channels. These cooperative effects are consistent with an inter-channel energetic repulsion due to the local membrane deformation created by the non-planar PIEZO structure. When channels open, this deformation shrinks, allowing open channels to diffuse closer to each other, thus delaying closure. This study reveals how PIEZO1 channels acquire their exceptional mechanosensitivity.

Treatment options to improve overall survival rate of prostate cancer patients are limited since tumor cells acquire resistance to the chemotherapeutic drugs. We aimed to determine anticancer effects of stone alkaline water (SAW) on PC--3 and DU--145 prostate adenocarcinoma cell lines. SAW was obtained by triturating high stones under vacuum at 3000 °C. High mineral and trace element containing fraction of SAW was used for the experiments. Viability of the tumor cells was analyzed using tetrazolium based WST--1 cell proliferation assay, cell cycle analysis was carried out with Propidum Iodide staining (Muse™ Cell Cycle Kit). Acridine Orange and Annexin V stainings were done to analyze the cellular morphology and to determine apoptosis. Tumor cell derived angiogenesis was analyzed with migration and tube formation assays. SAW treatment resulted in accumulation of cells at G0/G1 phase and inhibited tumor cell induced HUVEC tube formation and migration. SAW treatment significantly decreased viability of PC--3 and DU--145 prostate adenocarcinoma cells and induced apoptotic cell death.Intriguingly, treatment of the prostate cancer cells with SAW inhibited tumor cell derived angiogenesis. SAW may aid in treating prostate cancer and molecules important for SAW's apoptotic and anti--angiogenic effects need to be determined.