Emerging molecular mechanisms in chemotherapy: Ca2+ signaling at the mitochondria-associated endoplasmic reticulum membranes

Abstract

Inter-organellar communication often takes the form of Ca2+ signals. These Ca2+ signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca2+ signals are the mitochondria. ER–mitochondrial Ca2+ transfer is possible through the existence of mitochondria-associated ER membranes (MAMs), ER structures that are in the proximity of the mitochondria. This creates a micro-domain in which the Ca2+ concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca2+ uptake. In the mitochondria, the Ca2+ signal is decoded differentially depending on its spatiotemporal characteristics. While Ca2+ oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca2+ overload results in apoptosis. Many chemotherapeutics depend on efficient ER–mitochondrial Ca2+ signaling to exert their function. However, several oncogenes and tumor suppressors present in the MAMs can alter Ca2+ signaling in cancer cells, rendering chemotherapeutics ineffective. In this review, we will discuss recent studies that connect ER–mitochondrial Ca2+ transfer, tumor suppressors and oncogenes at the MAMs, and chemotherapy.

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

“…Considering this link between MAMs and Ca 2+ uptake, oncogenes and tumor suppressors may promote/prevent the survival of cancer cells by modulating MAMs size and hence the Ca 2+ exchanges that act as life and death signals (Bittremieux et al 2016;Danese et al 2017). Tethering proteins thus constitute a target of choice for chemotherapeutics (Kerkhofs et al 2018). In a general way, alterations of the spatial characteristics of the MAMs, and thus of Ca 2+ dynamics in these microdomains, potentially lead to various pathological disorders, such as obesity, neurodegenerative diseases, or cancers Pinton 2018).…”

The Calcium-Signaling Toolkit in Cancer: Remodeling and Targeting

“…There are also examples in which current agents used to treat cancer or those undergoing clinical trials act, at least in part, through Ca 2+ signaling to induce cancer cell death. This has been extensively reviewed elsewhere Bong and Monteith 2018;Kerkhofs et al 2018). One specific example of how Ca 2+ signaling and therapy intersect is seen in studies assessing the tumor suppressor p53 .…”

NFATC4 Promotes Quiescence and Chemotherapy Resistance in Ovarian Cancer

“…We demonstrated a mild increase in both RCAN1 and NFATC4 expression following Taxol treatment. This partial induction of RCAN1 mRNA may be a result of Taxol limited ability to increase intracellular calcium 30 , while increasing intracellular calcium is a key mechanism by which cisplatin functions 31 .…”