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Intracellular Ca2+ signals control several physiological and pathophysiological processes. The main tool to chelate intracellular Ca2+ is intracellular BAPTA (BAPTAi), usually introduced into cells as a membrane-permeant acetoxymethyl ester (BAPTA-AM). We previously demonstrated that BAPTAi enhanced apoptosis induced by venetoclax, a Bcl-2 antagonist, in diffuse large B-cell lymphoma (DLBCL). These findings implied a novel interplay between intracellular Ca2+ signaling and anti-apoptotic Bcl-2 function. Hence, we set out to identify the underlying mechanisms by which BAPTAi enhances cell death in B-cell cancers. In this study, we observed that BAPTAi alone induced apoptosis in lymphoma cell models that were highly sensitive to S63845, an Mcl-1 antagonist. BAPTAi provoked a rapid decline in Mcl-1 protein levels by inhibiting mTORC1-driven MCL-1 translation. Overexpression of nondegradable Mcl-1 rescued BAPTAi-induced cell death. We further examined how BAPTAi diminished mTORC1 activity and found that BAPTAi impaired glycolysis by directly inhibiting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) activity, an up to now unkown effect of BAPTAi. All aforementioned effects of BAPTAi were also elicited by a BAPTAi analog with low affinity for Ca2+. Thus, our work reveals PFKFB3 inhibition as an unappreciated Ca2+-independent mechanism by which BAPTAi impairs cellular metabolism and ultimately the survival of Mcl-1-dependent cancer cells. Our work has two important implications. First, direct inhibition of PFKFB3 emerged as a key regulator of mTORC1 activity and a promising target in the treatment of Mcl-1-dependent cancers. Second, cellular effects caused by BAPTAi are not necessarily related to Ca2+ signaling. Our data support the need for a reassessment of the role of Ca2+ in cellular processes when findings were based on the use of BAPTAi.

Membrane-contact sites are getting more and more credit for their indispensable role in maintenance of cell function and homeostasis. In the last decades, the ER-mitochondrial contact sites in particular received a lot of attention. While our knowledge of ER-mitochondrial contact sites increases steadily, the focus often lies on a static exploration of their functions. However, it is increasingly clear that these contact sites are very dynamic. In this review, we highlight the dynamic nature of ER-mitochondrial contact sites and the role of kinases and phosphatases therein with a focus on recent findings. Phosphorylation events allow for rapid integration of information on the protein level, impacting protein function, localization and interaction at ER-mitochondrial contact sites. To illustrate the importance of these events and to put them in a broader perspective, we connect them to pathologies like diabetes type II, Parkinson's disease and cancer.

Inositol 1,4,5-trisphosphate (IP

Bcl-2-protein family members are essential regulators of apoptosis. Anti-apoptotic Bcl-2 proteins ensure cell survival via different mechanisms, including via binding of pro-apoptotic Bcl-2-family members and the modulation of intracellular Ca2+-transport systems. Many cancer cells upregulate these proteins to overcome the consequences of ongoing oncogenic stress. Bcl-2 inhibition leading to cell death, therefore emerged as a novel cancer therapy. Different Bcl-2 inhibitors have already been developed including the hydrophobic cleft-targeting BH3 mimetics, which antagonize Bcl-2's ability to scaffold and neutralize pro-apoptotic Bcl-2-family members. As such, the BH3 mimetics have progressed into clinical studies as precision medicines. Furthermore, new inhibitors that target Bcl-2's BH4 domain have been developed as promising anti-cancer tools. Given Bcl-2's role in Ca2+ signaling, these drugs and tools can impact Ca2+ signaling. In addition to this, some Bcl-2 inhibitors may have "off-target" effects that cause Ca2+-signaling dysregulation not only in cancer cells but also in healthy cells, resulting in adverse effects. In this review, we aim to provide an up-to-date overview of the involvement of intracellular Ca2+ signaling in the working mechanism and "off-target" effects of the different Bcl-2-antagonizing small molecules and peptides. ispartof: Cell Calcium vol:70 pages:102-116 ispartof: location:Netherlands status: published

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.

Type 3 Inositol 1,4,5-trisphosphate (IP

Ca

Type 3 Inositol 1,4,5-trisphosphate (IP3) receptors (IP3R3s) have been identified as anti-oncogenic channels by propelling pro-apoptotic Ca2+ signals to mitochondria. Yet, recent studies (Rezuchova et al, Cell Death Dis, 2019; Ueasilamongkol et al, Hepathology, 2019; Guerra et al, Gut, 2019) revealed that IP3R3 upregulation drives oncogenesis via ER-mitochondrial Ca2+ crosstalk, adding complexity to IP3R3's role in cancer. ispartof: CELL CALCIUM vol:86 ispartof: location:Netherlands status: published

Ca2+ is a pleiotropic messenger that controls life and death decisions from fertilisation until death. Cellular Ca2+ handling mechanisms show plasticity and are remodelled throughout life to meet the changing needs of the cell. In turn, as the demands on a cell alter, for example through a change in its niche environment or its functional requirements, Ca2+ handling systems may be targeted to sustain the remodelled cellular state. Nowhere is this more apparent than in cancer. Oncogenic transformation is a multi-stage process during which normal cells become progressively differentiated towards a cancerous state that is principally associated with enhanced proliferation and avoidance of death. Ca2+ signalling is intimately involved in almost all aspects of the life of a transformed cell and alterations in Ca2+ handling have been observed in cancer. Moreover, this remodelling of Ca2+ signalling pathways is also required in some cases to sustain the transformed phenotype. As such, Ca2+ handling is hijacked by oncogenic processes to deliver and maintain the transformed phenotype. Central to generation of intracellular Ca2+ signals is the release of Ca2+ from the endoplasmic reticulum intracellular (ER) Ca2+ store via inositol 1,4,5-trisphosphate receptors (InsP3Rs). Upon depletion of ER Ca2+, store-operated Ca2+ entry (SOCE) across the plasma membrane occurs via STIM-gated Orai channels. SOCE serves to both replenish stores but also sustain Ca2+ signalling events. Here, we will discuss the role and regulation of these two signalling pathways and their interplay in oncogenic transformation. ispartof: Cell Calcium vol:82 ispartof: location:Netherlands status: Published online