Abstract
A apoptotic model was established based on the results of five hepatocellular carcinoma cell (HCC) lines irradiated with carbon ions to investigate the coupling interplay between apoptotic signaling and morphological and mechanical cellular remodeling. The expression levels of key apoptotic proteins and the changes in morphological characteristics and mechanical properties were systematically examined in the irradiated HCC lines. We observed that caspase-3 was activated and that the Bax/Bcl-2 ratio was significantly increased over time. Cellular morphology and mechanics analyses indicated monotonic decreases in spatial sizes, an increase in surface roughness, a considerable reduction in stiffness, and disassembly of the cytoskeletal architecture. A theoretical model of apoptosis revealed that mechanical changes in cells induce the characteristic cellular budding of apoptotic bodies. Statistical analysis indicated that the projected area, stiffness, and cytoskeletal density of the irradiated cells were positively correlated, whereas stiffness and caspase-3 expression were negatively correlated, suggesting a tight coupling interplay between the cellular structures, mechanical properties, and apoptotic protein levels. These results help to clarify a novel arbitration mechanism of cellular demise induced by carbon ions. This biomechanics strategy for evaluating apoptosis contributes to our understanding of cancer-killing mechanisms in the context of carbon ion radiotherapy.
Highlights
Coupling effect between cellular mechanical change and the activity of organized and composited signaling molecules in transduction pathways
Using theories from statistical physics, we propose a theoretical model to explain how the mechanical mechanism may control the budding process of apoptotic bodies (ABs) that accompany the modulation of apoptotic signaling
An approach based on immunoblotting (IB) was established to determine whether apoptotic proteins mediate the signals that initiate CII-induced apoptosis and to understand how apoptotic proteins participate in basic remodeling within a cell
Summary
Coupling effect between cellular mechanical change and the activity of organized and composited signaling molecules in transduction pathways. Biotype atomic force microscopy (AFM) provides a multifaceted platform to directly measure the mechanical parameters of a cell (such as cell elasticity, cell geometry and size, and the degree of cell surface roughness) and to study their responses to applied forces[22,23] This procedure allows quantitative investigations of how mechanical mechanisms are sensed by cells, and how the cells respond to applied forces and orchestrate the apoptotic remodeling process, which is characterized by changes in cell deformation and molecular damage events. Our results help to explain the different CII-induced apoptotic responses observed in different HCC lines by relating the responses to mechanical phenotypic signatures This evaluation of apoptosis based on biomechanics may facilitate the attainment of greater knowledge regarding cancer-killing mechanisms in the context of CII. Such knowledge may enable the expansion of previously described single biological strategies for cancer diagnosis and evaluation of the curative effect during therapy, especially in clinical hepatoma therapy, using CII
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