Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal

Mound, Abdallah; Vautrin-Glabik, Alexia; Foulon, Arthur; Botia, Béatrice; Hague, Frédéric; Parys, Jan B.; Ouadid-Ahidouch, Halima; Rodat-Despoix, Lise

doi:10.18632/oncotarget.20327

Cited by 45 publications

(53 citation statements)

References 58 publications

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“…Nevertheless, the function of the type 3 IP 3 Rs (IP 3 R3) is still elusive; both pro-apoptotic and anti-apoptotic effects were ascribed to this type of receptor 9–14 . Up to now, the expression of the IP 3 R3 subtype was shown to correlate with colorectal carcinoma aggressiveness 9 , or with increased cell migration capacities 12 . Inhibition of the IP 3 R3 subtype reduced breast cancer cell proliferation 10 , migration, invasion, and survival of glioblastoma cells 11 and revealed an oscillating Ca 2+ signature along with a slowing down cell migration in human breast cancer cells 12 .…”

Section: Introductionmentioning

confidence: 99%

Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells

et al. 2019

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Although the involvement of type 1 (IP3R1) and type 2 (IP3R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP3R (IP3R3) is still elusive. Therefore, in this work we focused on the role of IP3R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP3R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP3R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells. These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.

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Section: Introductionmentioning

confidence: 99%

Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells

et al. 2019

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“…The migration and invasion potential have been shown to be severely influenced by ITPR3 levels in other cancer cells. Whereas high levels of ITPR3 were observed in the highly migrating and invasive MDA-MB-231 and MDA-MB-435S breast cancer cell lines, the low-migrating MCF-7 showed low levels of ITPR3, but the stable overexpression of ITPR3 increased the migration capacity of this cell line [ 50 ]. In colorectal cancer DLD-1 cells, the silencing of ITPR3 expression led to a reduction of tumor volumes after injection of these cells in nude mice, increasing the apoptosis of these cells in hypoxic conditions and demonstrating the proliferative and anti-apoptotic role of ITPR3 [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells

Pascual-Caro

Orantos-Aguilera

Sanchez-Lopez

et al. 2020

IJMS

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STIM1 is an endoplasmic reticulum (ER) protein that modulates the activity of a number of Ca2+ transport systems. By direct physical interaction with ORAI1, a plasma membrane Ca2+ channel, STIM1 activates the ICRAC current, whereas the binding with the voltage-operated Ca2+ channel CaV1.2 inhibits the current through this latter channel. In this way, STIM1 is a key regulator of Ca2+ signaling in excitable and non-excitable cells, and altered STIM1 levels have been reported to underlie several pathologies, including immunodeficiency, neurodegenerative diseases, and cancer. In both sporadic and familial Alzheimer’s disease, a decrease of STIM1 protein levels accounts for the alteration of Ca2+ handling that compromises neuronal cell viability. Using SH-SY5Y cells edited by CRISPR/Cas9 to knockout STIM1 gene expression, this work evaluated the molecular mechanisms underlying the cell death triggered by the deficiency of STIM1, demonstrating that STIM1 is a positive regulator of ITPR3 gene expression. ITPR3 (or IP3R3) is a Ca2+ channel enriched at ER-mitochondria contact sites where it provides Ca2+ for transport into the mitochondria. Thus, STIM1 deficiency leads to a strong reduction of ITPR3 transcript and ITPR3 protein levels, a consequent decrease of the mitochondria free Ca2+ concentration ([Ca2+]mit), reduction of mitochondrial oxygen consumption rate, and decrease in ATP synthesis rate. All these values were normalized by ectopic expression of ITPR3 in STIM1-KO cells, providing strong evidence for a new mode of regulation of [Ca2+]mit mediated by the STIM1-ITPR3 axis.

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“…It has been revealed, that inhibition of ryanodine receptor subtype IP3R3 and subsequent decrease in Ca 2+ release results in suppression of the invasion and migration of glioblastoma cell lines and metastasis in glioblastoma mouse model (Kang et al, 2010). Overexpression of IP3R3, but not of IP3R1 and IP3R2, leads to stimulation of the migration properties of breast cancer cells sustaining Ca 2+ signaling (Mound et al, 2017). Thus, IP3R could regulate cancer cell migration and metastasis through modifying calcium ER level.…”

Section: Er-mitochondria Network and Metastasismentioning

confidence: 99%

Mitochondrial Involvement in Migration, Invasion and Metastasis

Denisenko

Горбунова

Zhivotovsky

2019

Front. Cell Dev. Biol.

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Mitochondria in addition to be a main cellular power station, are involved in the regulation of many physiological processes, such as generation of reactive oxygen species, metabolite production and the maintenance of the intracellular Ca 2+ homeostasis. Almost 100 years ago Otto Warburg presented evidence for the role of mitochondria in the development of cancer. During the past 20 years mitochondrial involvement in programmed cell death regulation has been clarified. Moreover, it has been shown that mitochondria may act as a switchboard between various cell death modalities. Recently, accumulated data have pointed to the role of mitochondria in the metastatic dissemination of cancer cells. Here we summarize the modern knowledge concerning the contribution of mitochondria to the invasion and dissemination of tumor cells and the possible mechanisms behind that and attempts to target metastatic cancers involving mitochondria.

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Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal

Cited by 45 publications

References 58 publications

Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells

Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells

STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells

Mitochondrial Involvement in Migration, Invasion and Metastasis

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