Various Aspects of Calcium Signaling in the Regulation of Apoptosis, Autophagy, Cell Proliferation, and Cancer

Abstract

Calcium (Ca2+) is a major second messenger in cells and is essential for the fate and survival of all higher organisms. Different Ca2+ channels, pumps, or exchangers regulate variations in the duration and levels of intracellular Ca2+, which may be transient or sustained. These changes are then decoded by an elaborate toolkit of Ca2+-sensors, which translate Ca2+ signal to intracellular operational cell machinery, thereby regulating numerous Ca2+-dependent physiological processes. Alterations to Ca2+ homoeostasis and signaling are often deleterious and are associated with certain pathological states, including cancer. Altered Ca2+ transmission has been implicated in a variety of processes fundamental for the uncontrolled proliferation and invasiveness of tumor cells and other processes important for cancer progression, such as the development of resistance to cancer therapies. Here, we review what is known about Ca2+ signaling and how this fundamental second messenger regulates life and death decisions in the context of cancer, with particular attention directed to cell proliferation, apoptosis, and autophagy. We also explore the intersections of Ca2+ and the therapeutic targeting of cancer cells, summarizing the therapeutic opportunities for Ca2+ signal modulators to improve the effectiveness of current anticancer therapies.

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

“…Under IS conditions, due to the high levels of extracellular glutamate, cells in the penumbra are subjected to hyperactivation of glutamate receptors, promoting a substantial influx of Ca 2+ into the cells [ 47 , 48 , 49 ]. Ca 2+ ions, as second messengers, have been associated with cell death and survival [ 50 , 51 , 52 ] and are implicated in several pathologies [ 53 , 54 ]. Mitochondria are strictly connected to Ca 2+ signaling and are key actors in buffering cytosolic Ca 2+ levels [ 54 , 55 , 56 ].…”

TRPM4 in Cancer—A New Potential Drug Target

“…The drop in ER luminal Ca 2+ concentration sequentially activates the unfolding of stromal interaction molecule 1 (STIM1) and, subsequently, activates the store-operated Orai1 Ca 2+ channels [ 52 ]. Anticancer drugs may involve changes in Ca 2+ signaling [ 53 , 54 ]; moreover, membrane transport proteins contribute to chemoresistance in several types of cancer [ 55 ]. Although TRPM4 is nonpermeable to Ca 2+ , Na + influx via TRPM4 decreases membrane potential and results in a decrease in intracellular Ca 2+ signaling in many different cells, including rat dental pulp stem cells, various immune cells, and cancer cells [ 2 , 12 , 13 , 14 , 41 , 56 , 57 ].…”

Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases

“…Mitochondria are essential semi-autonomous cellular organelles with a double membrane composed by an inner (IMM) and an outer membrane (OMM). OMM separates the mitochondria from cytoplasm and it may be freely traversed by many proteins (5000 daltons or less), ions, such as Calcium (Ca 2+ ), and metabolites, while the larger molecules are imported by specific translocase [ 10 , 11 , 12 ]. IMM is highly specialized and permits the passage of small molecules, including oxygen, carbon dioxide, and water.…”