The bioelectric mechanisms of local calcium dynamics in cancer cell proliferation: An extension of the A549 in-silico cell model

Introduction: Advances in molecular targeting of ion channels may open up new
avenues for therapeutic approaches in cancer based on the cells’ bioelectric
properties. In addition to in-vitro or in-vivo models, in silico models can provide
deeper insight into the complex role of electrophysiology in cancer and reveal the
impact of altered ion channel expression and the membrane potential on malignant
processes. The A549 in silico model is the first computational cancer whole-cell ion
current model that simulates the bioelectric mechanisms of the human non-small
cell lung cancer cell line A549 during the different phases of the cell cycle. This work
extends the existing model with a detailed mathematical description of the storeoperated
Ca2+ entry (SOCE) and the complex local intracellular calcium dynamics,
which significantly affect the entire electrophysiological properties of the cell and
regulate cell cycle progression.
Methods: The initial model was extended by a multicompartmental approach,
addressing the heterogenous calcium profile and dynamics in the ER-PM junction
provoked by local calcium entry of store-operated calcium channels (SOCs) and
uptake by SERCA pumps. Changes of cytosolic calcium levels due to diffusion from
the ER-PM junction, release fromthe ER by RyR channels and IP3 receptors, as well as
corresponding PM channels were simulated and the dynamics evaluated based on
calcium imaging data. The model parameters were fitted to available data from two
published experimental studies, showing the function of CRAC channels and
indirectly of IP3R, RyR and PMCA via changes of the cytosolic calcium levels.
Results: The proposed calcium description accurately reproduces the dynamics of
calcium imaging data and simulates the SOCE mechanisms. In addition, simulations
of the combined A549-SOCE model in distinct phases of the cell cycle demonstrate
how Ca2+ - dynamics influence responding channels such as KCa, and consequently
modulate the membrane potential accordingly.
Discussion: Local calcium distribution and time evolution in microdomains of the
cell significantly impact the overall electrophysiological properties and exert
control over cell cycle progression. By providing a more profound description, the
extended A549-SOCE model represents an important step on the route towards a
valid model for oncological research and in silico supported development of novel
therapeutic strategies.