Ca2+ as a therapeutic target in cancer

Gross, Scott; Mallu, Pranava; Joshi, Hinal; Schultz, Bryant M.; Go, Christina; Soboloff, Jonathan

doi:10.1016/bs.acr.2020.05.003

Cited by 20 publications

(19 citation statements)

References 504 publications

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“…Ca 2+ is a dynamic second messenger induced by many factors, leading to pleiotropic effects on cell survival including changes of migration, proliferation, and metabolism. Thus, it is not surprising that aberrant regulation of Ca 2+ signals can lead to pathological phenotypes, including cancer progression [ 19 ]. However, given the highly context-specific nature of Ca 2+ dependent changes in tumor cell function, its role in the TME needs to be further explored.…”

Section: Resultsmentioning

confidence: 99%

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

Gao

Liu

et al. 2021

Cell Death Dis

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It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

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Section: Resultsmentioning

confidence: 99%

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

Gao

Liu

et al. 2021

Cell Death Dis

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“…Likewise, qPCR data revealed slightly higher PLD1 than PLD2 expression levels in MDA-NEO and MDA-HER2 cells, which is in agreement with data of Kim et al showing a similar PLD1/PLD2 expression profile in MDA-MB-468 wild type, from which MDA-NEO and MDA-HER2 cells were derived. Calcium is a universal second messenger that is involved in various cellular processes, including proliferation, apoptosis, transcription, metabolism and cell migration [ 6 , 13 , 19 ]. In this regard, we and others have already demonstrated the crucial interplay of RTK-mediated PLC-γ1 activation, the release of calcium from intracellular stores, the reorganization of the actin cytoskeleton and cell migration [ 3 , 12 , 32 , 40 , 48 , 52 , 56 , 62 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…If so, this would mean that both PA and choline would play a role in the EGF-induced and PLC-γ1-dependent release of calcium from intracellular stores. Calcium is a versatile second messenger that is involved in various cellular processes, including cell migration [ 6 , 13 , 19 ]. Hence, the abrogation of calcium signaling by FIPI is one explanation for the observed reduced migration of the cells in the presence of this inhibitor.…”

Section: Discussionmentioning

confidence: 99%

The phospholipase D inhibitor FIPI potently blocks EGF-induced calcium signaling in human breast cancer cells

et al. 2021

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Background Phosphotyrosine kinase (PTK)-mediated phospholipase C-γ1 (PLC-γ1) signaling plays a crucial role in the release of the universal second messenger calcium from intracellular stores, which is mandatory for several cellular processes, including cell migration. However, PLC-γ1 could also be activated in a PTK-independent manner by phospholipase D (PLD)-derived phosphatidic acid (PA). Because both higher PLD expression levels and PLD activity have also been associated with breast cancer cell invasion and migration, we wondered whether there might be a link between PLD and PLC-γ1, which was investigated in this study. Materials MDA-MB-468-NEO (EGFR positive) and MDA-MB-468-HER2 (EGFR and HER2 positive) human breast cancer cells were used in this study. The migratory behavior of the cells in the presence of epidermal growth factor (EGF) and the PLD inhibitor 5-fluoro-2-indolyl-des-chlorohalopemide (FIPI) was analyzed using the 3D collagen matrix migration assay. Changes in cytosolic calcium levels in the presence of EGF, FIPI and Sig-1R agonists and antagonists as well as in PLD1 siRNA knockdown cells were determined by flow cytometry. Western blot analyses were performed to determine the basal expression levels and phosphorylation patterns of EGFR, HER2, AKT, MAPKp42/44, PLC-γ1 and Sig-1R. Results The EGF-induced migration of MDA-MB-468-NEO and MDA-MB-468-HER2 cells was significantly impaired by FIPI. Likewise, FIPI also significantly abolished EGF-induced calcium release in both cell lines. However, neither the expression levels nor the phosphorylation patterns of EGFR, HER2, AKT, MAPKp42/44 and PLC-γ1 were markedly changed by FIPI. Knockdown of PLD1 expression by siRNA also significantly impaired EGF-induced calcium release in both cell lines. Targeting Sig-1R, which interacts with IP3R, with the antagonist BD1047 also abrogated EGF-induced calcium release. However, EGF-induced calcium release was also impaired if cells were treated with the Sig-1R agonists PRE084 and PPBP maleate. Conclusion In summary, blocking PLD activity with the specific inhibitor FIPI or knocking down PDL1 expression by siRNA significantly impaired EGF-induced calcium release in MDA-MB-468-NEO and MDA-MB-468-HER2 cells, likely indicating a connection between PLD activity and PLC-γ1-mediated calcium signaling. However, how PLD activity interferes with the release of calcium from intracellular stores remains unclear.

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Section: Role Of Ion Channels In Cancer Cells and Host-tumour Cross-talkmentioning

confidence: 99%

“…Intracellular Ca 2+ homeostasis disruption, and aberrant activation of downstream signalling pathways is a well-established cause of cancerous transformation ( Gross et al, 2020 ). Tajada and Villalobos summarized the expression profile of voltage-gated Ca 2+ channels (Ca V 1.2, Ca V 1.3, Ca V 1.4, Ca V 2.1, Ca V 2.2, Ca V 3.1, Ca V 3.2, Ca V 3.3), transient receptor potential channels (TRPC1, TRPC3, TRPC4, TRPV4, TRPV6, TRPM6, TRPM7, TRPM8), and Ca 2+ release activated Ca 2+ or store-operated Ca 2+ (CRAC/SOC) channels (ORAI1, ORAI3) in various cancer types.…”

Section: Role Of Ion Channels In Cancer Cells and Host-tumour Cross-talkmentioning

confidence: 99%

Editorial: Ion Channel Signalling in Cancer: From Molecular Mechanisms to Therapeutics

2021

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Mammalian cells express a large number of structurally distinct ion channels on the cell surface and also in the membranes of intracellular organelles. They can selectively permeate ion species (thus named Ca 2+ , Na + , K + or Cl − channels according to their selectivity) or a group of positively or negatively charged ions (non-selective cation or anion channels) (Hille, 2001). Their activity is regulated by diverse physical, biochemical or biological stimuli of the microenvironments and, as such, they initial or control important signaling mechanisms involved in a wide range of cellular processes which are critical for cancer development and progression including cell differentiation, proliferation, migration and apoptosis. It comes no surprise that an alteration in ion channel expression and/or activity is causatively associated with manifestation of cancer hallmarks (Hanahan and Weinberg, 2011), leading to the introduction of oncochannels (Huber, 2013).This Research Topic collects 16 review and original research articles, which provide ideaprovoking insights or new research regarding the role of ion channels in cancer and the concept or efforts of targeting them to treat cancer. ROLE OF ION CHANNELS IN CANCER CELLS AND HOST-TUMOUR CROSS-TALKIntracellular Ca 2+ homeostasis disruption, and aberrant activation of downstream signalling pathways is a well-established cause of cancerous transformation (Gross et al., 2020). Tajada and Villalobos summarized the expression profile of voltage-gated Ca 2+ channels

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Ca2+ as a therapeutic target in cancer

Cited by 20 publications

References 504 publications

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

The phospholipase D inhibitor FIPI potently blocks EGF-induced calcium signaling in human breast cancer cells

Editorial: Ion Channel Signalling in Cancer: From Molecular Mechanisms to Therapeutics

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