Editorial

Ca²⁺ signaling and cell death: Focus on the role of Ca²⁺ signals in the regulation of cell death & survival processes in health, disease and therapy

Ion channels play a crucial role in cellular signaling, homeostasis, and generation of electrical and chemical signals. Aberrant expression and dysregulation of ion channels have been associated with cancer development and resistance to conventional cancer treatment such as chemotherapy. Several molecular mechanisms have been proposed to explain this phenomenon. Including evasion of apoptosis, decreased drug accumulation in cancer cells, detoxifying and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. This review highlights the linkages between ion channels and resistance to chemotherapy. Furthermore, it elaborates their molecular mechanisms and the potential of being therapeutic targets in clinical management.

Fumarylacetoacetate hydrolase (FAH) superfamily members are commonly expressed in the prokaryotic kingdom, where they take part in the committing steps of degradation pathways of complex carbon sources. Besides FAH itself, the only described FAH superfamily members in the eukaryotic kingdom are fumarylacetoacetate hydrolase domain containing proteins (FAHD) 1 and 2, that have been a focus of recent work in aging research. Here, we provide a review of current knowledge on FAHD proteins. Of those, FAHD1 has recently been described as a regulator of mitochondrial function and senescence, in the context of mitochondrial dysfunction associated senescence (MiDAS). This work further describes data based on bioinformatics analysis, 3D structure comparison and sequence alignment, that suggests a putative role of FAHD proteins as calcium binding proteins.

Inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs), intracellular calcium (Ca²⁺) release channels, fulfill key functions in cell death and survival processes, whose dysregulation contributes to oncogenesis. This is essentially due to the presence of IP₃Rs in microdomains of the endoplasmic reticulum (ER) in close proximity to the mitochondria. As such, IP₃Rs enable efficient Ca²⁺ transfers from the ER to the mitochondria, thus regulating metabolism and cell fate. This review focuses on one of the three IP₃R isoforms, the type 3 IP₃R (IP₃R3), which is linked to proapoptotic ER-mitochondrial Ca²⁺ transfers. Alterations in IP₃R3 expression have been highlighted in numerous cancer types, leading to dysregulations of Ca²⁺ signaling and cellular functions. However, the outcome of IP₃R3-mediated Ca²⁺ transfers for mitochondrial function is complex with opposing effects on oncogenesis. IP₃R3 can either suppress cancer by promoting cell death and cellular senescence or support cancer by driving metabolism, anabolic processes, cell cycle progression, proliferation and invasion. The aim of this review is to provide an overview of IP₃R3 dysregulations in cancer and describe how such dysregulations alter critical cellular processes such as proliferation or cell death and survival. Here, we pose that the IP₃R3 isoform is not only linked to proapoptotic ER-mitochondrial Ca²⁺ transfers but might also be involved in prosurvival signaling.

ROCO kinases form a family of proteins characterized by kinase activity in addition to the presence of the so-called ROC (Ras of complex proteins)/COR (C-terminal of ROC) domains having a role in their GTPase activity. These are the death-associated protein kinase (DAPK) 1 and the leucine-rich repeat kinases (LRRK) 1 and 2. These kinases all play roles in cellular life and death decisions and in autophagy in particular. Related to the ROCO kinases is DAPK 2 that however cannot be classified as a ROCO protein due to the absence of the ROC/COR domains. This review aims to bring together what is known about the relation between these proteins and intracellular Ca²⁺ signals in the induction and regulation of autophagy. Interestingly, DAPK 1 and 2 and LRRK2 are all linked to Ca²⁺ signaling in their effects on autophagy, though in various ways. Present evidence supports an upstream role for LRRK2 that via lysosomal and endoplasmic reticulum Ca²⁺ release can trigger autophagy induction. In contrast herewith, DAPK1 and 2 react on existing Ca²⁺ signals to stimulate the autophagic pathway. Further research will be needed for obtaining a full understanding of the role of these various kinases in autophagy and to assess their exact relation with intracellular Ca²⁺ signaling as this would be helpful in the development of novel therapeutic strategies against neurodegenerative disorders, cancer and auto-immune diseases.

This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.