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Review
. 2022 Sep 14;23(18):10687.
doi: 10.3390/ijms231810687.

Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance

Sana Kouba  1 , Frédéric Hague  1 , Ahmed Ahidouch  1   2 , Halima Ouadid-Ahidouch  1
Affiliations
Review

Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance

Sana Kouba et al. Int J Mol Sci. .

Abstract

In the fight against cancer, therapeutic strategies using cisplatin are severely limited by the appearance of a resistant phenotype. While cisplatin is usually efficient at the beginning of the treatment, several patients endure resistance to this agent and face relapse. One of the reasons for this resistant phenotype is the emergence of a cell subpopulation known as cancer stem cells (CSCs). Due to their quiescent phenotype and self-renewal abilities, these cells have recently been recognized as a crucial field of investigation in cancer and treatment resistance. Changes in intracellular calcium (Ca2+) through Ca2+ channel activity are essential for many cellular processes such as proliferation, migration, differentiation, and survival in various cell types. It is now proved that altered Ca2+ signaling is a hallmark of cancer, and several Ca2+ channels have been linked to CSC functions and therapy resistance. Moreover, cisplatin was shown to interfere with Ca2+ homeostasis; thus, it is considered likely that cisplatin-induced aberrant Ca2+ signaling is linked to CSCs biology and, therefore, therapy failure. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to a range of pressures dictates the global degree of cisplatin resistance. However, if we can understand the molecular mechanisms linking Ca2+ to cisplatin-induced resistance and CSC behaviors, alternative and novel therapeutic strategies could be considered. In this review, we examine how cisplatin interferes with Ca2+ homeostasis in tumor cells. We also summarize how cisplatin induces CSC markers in cancer. Finally, we highlight the role of Ca2+ in cancer stemness and focus on how they are involved in cisplatin-induced resistance through the increase of cancer stem cell populations and via specific pathways.

Keywords: calcium channels; calcium signaling; cancer stem cells; chemoresistance; cisplatin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A brief overview of the pathways involved in mediating cisplatin-induced effects in cells. Apoptosis as well as cell survival depend on the nature and intensity of the signals generated and the crosslinks between the pathways involved. Apoptosis is initiated following the recognition of DNA damage by candidate proteins that bind to physical distortions in the DNA induced by cisplatin. When DNA damage is detected and cannot be repaired, the activation of the irreversible intrinsic death pathway mediated by p53 occurs. Depending on the intensity of DNA damage, the cell cycle is arrested at checkpoints that prevent its progression for DNA repair and cell survival. Abbreviations: ATR: ataxia telangiectasia and Rad3-related protein; Akt: protein kinase B; Bax: Bcl-2–associated X; Chk1/2: checkpoint kinases 1 and 2; C-Abl: tyrosine-protein kinase ABL1; casp: caspase; Cyt c: cytochrome c; Fas/FasL: Fas–Fas Ligand; GADD45a: growth arrest and DNA damage-inducible alpha; MAPK: mitogen-activated protein kinases Mdm2: mouse double-minute 2; PI3K: phosphoinositide 3-kinase; p73: tumor suppressor p53-related protein; p53: tumor suppressor protein; p21: cyclin-dependent kinase inhibitor.
Figure 2
Figure 2
Ca2+ homeostasis in non-excitable cells. Agonists bind to their receptors (GPCR or TK), which are located at the plasma membrane (PM), thereby activating PLC. The hydrolysis of phosphatidylinositol 4,5-biphosphate leads to the production of IP3 and the release of Ca2+ from the ER store via IP3R. ER store depletion activates the STIM proteins, which translocate to ER–PM junctions and gate heterohexamer ORAI channels. Ca2+ influx activates a set of proteins and effectors that are responsible for gene transcription. Calcium homeostasis is maintained by PM and organelle channels, transporters, and exchangers. Abbreviations: CaM: calmodulin; DAG: diacylglycerol; ER: endoplasmic reticulum; GPCR: G protein-coupled receptor; IP3R: inositol 1,4,5-trisphosphate receptor; Mt: mitochondria; MCU: mitochondrial Ca2+ uniporter; NCX: Na+/Ca2+ exchanger; NCLX: Na+/Ca2+/Li+ exchanger; NFAT: nuclear factor of activated T-cells; PLC: phospholipase C; PMCA: plasma membrane Ca2+ ATPase; PtdIns(4,5)P2: phosphatidylinositol 4,5-bisphosphate; RTK: receptor tyrosine kinase; SERCA: sarco-/endoplasmic reticulum Ca2+-ATPase; STIM: stromal interaction molecule. This figure was created using www.biorender.com.
Figure 3
Figure 3
Summary of cisplatin-mediated resistance through Ca2+ signaling and stemness. Chronic cisplatin exposure affects the expression of Ca2+ channels and other Ca2+ homeostatic proteins. On the one hand, the altered Ca2+ fluxes activate Ca2+-dependent pathways that are involved in the survival of cancer cells, such as the inhibition of apoptosis and enhancement of autophagy. On the other hand, stem-related Ca2+-dependent transcription factors are activated, participating in the enrichment of CSC populations and their maintenance, which promotes tumor re-development. This figure was created with www.biorender.com.
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