Abstract
Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+-signaling and loss of [Ca2+]i homeostasis contributes to tumor initiation proliferation, angiogenesis, and other key processes that support tumor progression in several different cancers. Currently, chemically and functionally distinct drugs are used as chemotherapeutic agents in the treatment and management of cancer among which certain anti-cancer drugs reportedly suppress pro-survival signals and activate pro-apoptotic signaling through modulation of Ca2+-signaling-dependent mechanisms. Most importantly, the modulation of [Ca2+]i levels via the endoplasmic reticulum-mitochondrial axis and corresponding action of channels and pumps within the plasma membrane play an important role in the survival and death of cancer cells. The endoplasmic reticulum-mitochondrial axis is of prime importance when considering Ca2+-signaling-dependent anti-cancer drug targets. This review discusses how calcium signaling is targeted by anti-cancer drugs and highlights the role of calcium signaling in epigenetic modification and the Warburg effect in tumorigenesis.
Highlights
Abnormalities in [Ca2+]i-signaling are associated with various cancers and is implicated in therapy resistance [23,24,25]
It is shown that down-regulation of mitochondrial calcium uniporter (MCU) in human colon cancer cells correlates with miR-25 aberrant expression, pointing the importance of mitochondrial Ca2+ regulation in apoptosis
In the context of cancer, many drugs such as CDDP, topotecan, and As2O3 induce apoptosis depending on extra- and intracellular calcium
Summary
Intracellular calcium ([Ca2+]i) is an important second messenger involved in cellular functions of muscles, neurons, immune cells, oocytes and others, modulating enzyme secretion, gene activation, proliferation, apoptosis, cell cycle progression, fertilization, and release of neurotransmitters [1,2,3]. In this review we analyze the anti-cancer action of selected agents targeting the calcium dependent pathways regulating proliferation and apoptosis. The mechanism behind Ca2+-induced cell proliferation involves the interaction of estrogen binding to G-protein coupled estrogen receptor (GPER) causing the L-type channel to open and allow Ca2+-entry, followed by downstream activation of the ERK1/2-CREB pathway promoting cell proliferation. The silencing of G protein-coupled estrogen receptor 30 (GPER1/GPR30) mediated via siRNA transfection abolished Ca2+-influx as well as proliferation in BC, which may be an indication of a crucial role of Ca2+ entry through L-type channels in cell proliferation and breast cancer progression [29]. Store operated calcium channels (SOC) on the plasma membrane generate calcium signals in a variety of cell types [43] and are considered to be the main calcium entry in non-excitable cells. As the SOC entry is considered to be primary Ca2+ entry mechanism in most cancer types ( contributing to cancer cell migration, invasiveness, and metastasis), there is a high interest in development of selective SOC entry blockers to prevent cancer metastasis [52,53]
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