The ER-mitochondria Ca2+ signaling in cancer progression: Fueling the monster

Bustos, Galdo; Ahumada-Castro, Ulises; Silva-Pavez, Eduardo; Puebla, Andrea Fabiana; Lovy, Alenka; Cárdenas, José Miguel

doi:10.1016/bs.ircmb.2021.03.006

Cited by 18 publications

(10 citation statements)

References 466 publications

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“…Additionally, we established that CIDD-99 not only decreased, calcium entry, but also decreased ER calcium levels, which induces ER stress that can modulate apoptosis in oral cancer cells. Interestingly, mitochondrial function was also inhibited by the addition of CIDD-99, which can again be due to the loss of calcium homeostasis, as recent studies have shown that mitochondria and ER crosstalk determine the cell fate by modulating mitochondrial Ca 2+ homeostasis and metabolism ( Missiroli et al, 2017 ; Bustos et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation

et al. 2022

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Oral cancer patients have a poor prognosis, with approximately 66% of patients surviving 5-years after diagnosis. Treatments for oral cancer are limited and have many adverse side effects; thus, further studies are needed to develop drugs that are more efficacious. To achieve this objective, we developed CIDD-99, which produces cytotoxic effects in multiple oral squamous cell carcinoma (OSCC) cell lines. While we demonstrated that CIDD-99 induces ER stress and apoptosis in OSCC, the mechanism was unclear. Investigation of the Bcl-family of proteins showed that OSCC cells treated with CIDD-99 undergo downregulation of Bcl-XL and Bcl-2 anti-apoptotic proteins and upregulation of Bax (pro-apoptotic). Importantly, OSCC cells treated with CIDD-99 displayed decreased calcium signaling in a dose and time-dependent manner, suggesting that blockage of calcium signaling is the key mechanism that induces cell death in OSCC. Indeed, CIDD-99 anti-proliferative effects were reversed by the addition of exogenous calcium. Moreover, electrophysiological properties further established that calcium entry was via the non-selective TRPC1 channel and prolonged CIDD-99 incubation inhibited STIM1 expression. CIDD-99 inhibition of calcium signaling also led to ER stress and inhibited mitochondrial complexes II and V in vitro. Taken together, these findings suggest that inhibition of TRPC mediates induction of ER stress and mitochondrial dysfunction as a part of the cellular response to CIDD-99 in OSCC.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation

et al. 2022

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“…These observations suggest that enhanced ER-to-mitochondria Ca 2+ transfer may be a feature associated with many types of cancer. Transformation also facilitated a rapid stimulation of respiration in response to an acute cytoplasmic Ca 2+ signal, which may be crucial for energy regulation to sustain increased bioenergetic demand during cancer progression (Cardenas et al, 2010;Koval et al, 2019;Bustos et al, 2021;Herst et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial Ca²⁺channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation

Garcia

Paudel

Noji

et al. 2023

Preprint

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The mitochondrial uniporter (MCU) Ca2+ion channel represents the primary means for Ca2+uptake into mitochondria. Here we employedin vitroandin vivomodels with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblastsin vitrowas associated with increased MCU expression, enhanced mitochondrial Ca2+uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca2+-dependent stimulation of mitochondrial respiration. Inhibition of mitochondrial Ca2+uptake by genetic deletion of MCU markedly inhibited growth of HEK293T cells and of transformed fibroblasts in mouse xenograft models. Reduced tumor growth was primarily a result of substantially reduced proliferation and fewer mitotic cellsin vivo, and slower cell proliferationin vitroassociated with delayed progression through S-phase of the cell cycle. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasionin vitro, both predictors of metastatic potential. Surprisingly, mitochondrial matrix Ca2+content, membrane potential, global dehydrogenase activity, respiration and ROS production were unchanged by genetic deletion of MCU in transformed cells. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca2+signals. Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on mitochondrial Ca2+uptake for cell metabolism and Ca2+dynamics necessary for cell-cycle progression and cell proliferation.

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“…Indeed, the transgene-enforced overexpression of CALR has been shown to sensitize radioresistant human glioblastoma U251MG and T98G to ionizing radiation, at least partially via a mechanism that involves reduced pro-survival signaling via AKT serine/threonine kinase 1 (AKT1) coupled with disruption of intracellular Ca 2+ homeostasis. [90][91][92][93][94] Taken together, these observations suggest that irradiated cancer cells may experience perturbations of reticular homeostasis coupled with the activation of an adaptive response culminating with the upregulation of CALR and its exposure to the cell surface in support of increased adjuvanticity. Moreover, CALR appears to promote intrinsic radiosensitivity, at least in some experimental settings.…”

Section: Alre Ti Culinmentioning

confidence: 92%

Molecular determinants of immunogenic cell death elicited by radiation therapy

Galassi,

Klapp,

Yamazaki

et al. 2023

Immunological Reviews

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SummaryCancer cells undergoing immunogenic cell death (ICD) can initiate adaptive immune responses against dead cell‐associated antigens, provided that (1) said antigens are not perfectly covered by central tolerance (antigenicity), (2) cell death occurs along with the emission of immunostimulatory cytokines and damage‐associated molecular patterns (DAMPs) that actively engage immune effector mechanisms (adjuvanticity), and (3) the microenvironment of dying cells is permissive for the initiation of adaptive immunity. Finally, ICD‐driven immune responses can only operate and exert cytotoxic effector functions if the microenvironment of target cancer cells enables immune cell infiltration and activity. Multiple forms of radiation, including non‐ionizing (ultraviolet) and ionizing radiation, elicit bona fide ICD as they increase both the antigenicity and adjuvanticity of dying cancer cells. Here, we review the molecular determinants of ICD as elicited by radiation as we critically discuss strategies to reinforce the immunogenicity of cancer cells succumbing to clinically available radiation strategies.

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The ER-mitochondria Ca2+ signaling in cancer progression: Fueling the monster

Cited by 18 publications

References 466 publications

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation

The mitochondrial Ca²⁺channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation

Molecular determinants of immunogenic cell death elicited by radiation therapy

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The ER-mitochondria Ca2+ signaling in cancer progression: Fueling the monster

Cited by 18 publications

References 466 publications

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation

The mitochondrial Ca2+channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation

Molecular determinants of immunogenic cell death elicited by radiation therapy

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Product

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The mitochondrial Ca²⁺channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation