Functional role of TRPC6 and STIM2 in cytosolic and endoplasmic reticulum Ca2+ content in resting estrogen receptor-positive breast cancer cells

Sánchez-Collado, José; López, José J.; Gonzalez-Gutierrez, Lucia; Cantonero, Carlos; Jardín, Isaac; Salido, Ginés M.; Rosado, Juan A.

doi:10.1042/bcj20200560

Cited by 13 publications

(16 citation statements)

References 31 publications

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“…Altogether, these findings indicate that TRPC6 is involved in constitutive Ca 2+ entry in ppFurin-expressing MDA-MB-231 cells. Recent studies have reported constitutive activity of STIM2 in resting conditions [27,28]. Hence, we have investigated whether STIM2 expression is altered in ppFurin-expressing cells or upon TRPC6 expression silencing.…”

Section: Regulation Of Ca 2+ Mobilization By Ppfurinmentioning

confidence: 99%

Furin Prodomain ppFurin Enhances Ca2+ Entry Through Orai and TRPC6 Channels’ Activation in Breast Cancer Cells

López

Siegfried

Cantonero

et al. 2021

Cancers

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The intracellular calcium concentration ([Ca2+]i) modulation plays a key role in the regulation of cellular growth and survival in normal cells and failure of [Ca2+]i homeostasis is involved in tumor initiation and progression. Here we showed that inhibition of Furin by its naturally occurring inhibitor the prodomain ppFurin in the MDA-MB-231 breast cancer cells resulted in enhanced store-operated calcium entry (SOCE) and reduced the cell malignant phenotype. Expression of ppFurin in a stable manner in MDA-MB-231 and the melanoma MDA-MB-435 cell lines inhibits Furin activity as assessed by in vitro digestion assays. Accordingly, cell transfection experiments revealed that the ppFurin-expressing cells are unable to adequately process the proprotein convertase (PC) substrates vascular endothelial growth factor C (proVEGF-C) and insulin-like growth factor-1 receptor (proIGF-1R). Compared to MDA-MB-435 cells, expression of ppFurin in MDA-MB-231 and BT20 cells significantly enhanced SOCE and induced constitutive Ca2+ entry. The enhanced SOCE is impaired by inhibition of Orai channels while the constitutive Ca2+ entry is attenuated by silencing or inhibition of TRPC6 or inhibition of Orai channels. Analysis of TRPC6 activation revealed its upregulated tyrosine phosphorylation in ppFurin-expressing MDA-MB-231 cells. In addition, while ppFurin had no effect on MDA-MB-435 cell viability, in MDA-MB-231 cells ppFurin expression reduced their viability and ability to migrate and enhanced their sensitization to the apoptosis inducer hydrogen peroxide and similar results were observed in BT20 cells. These findings suggest that Furin inhibition by ppFurin may be a useful strategy to interfere with Ca2+ mobilization, leading to breast cancer cells’ malignant phenotype repression and reduction of their resistance to treatments.

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Section: Regulation Of Ca 2+ Mobilization By Ppfurinmentioning

confidence: 99%

Furin Prodomain ppFurin Enhances Ca2+ Entry Through Orai and TRPC6 Channels’ Activation in Breast Cancer Cells

López

Siegfried

Cantonero

et al. 2021

Cancers

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“…In contrast to Orai1, its homologue Orai3 is not sensitive to ROS, and the Orai1/Orai3 ratio determines if intracellular SOCE Ca 2+ signaling depend on ROS [65][66][67][68]. Both STIM2 and Orai3 subunits are dysregulated in different types of cancer and contribute to metastatic spread, proliferation, and reduced apoptosis [43,[67][68][69][70][71][72][73][74][75][76][77][78][79][80]. TRPM4 directly contributes to H 2 O 2 -dependent migration, possibly because H 2 O 2 prevents the desensi-tization of TRPM4 [59,81].…”

Section: General Mechanisms Of Trpm4mentioning

confidence: 99%

TRPM4 in Cancer—A New Potential Drug Target

2021

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Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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“…SOCE in MCF7, as well as in other ER+ breast cancer cell lines, exhibits significant phenotypic and functional differences compared to other cell types. For instance, while the expression of STIM1 in these cells is normal or low, STIM2 expression is slightly higher, and both Orai1 and Orai3 are overexpressed, especially Orai3 [9,10,28]. From the functional point of view, SOCE in MCF7 is mediated by STIM1, STIM2, and Orai3, in contrast to other breast cancer subtypes, such as TNBC cells, where SOCE is entirely dependent on STIM1 and Orai1 [9,10].…”

Section: Discussionmentioning

confidence: 91%

SARAF and EFHB Modulate Store-Operated Ca2+ Entry and Are Required for Cell Proliferation, Migration and Viability in Breast Cancer Cells

Jardín

Nieto‐Felipe

Alvarado

et al. 2021

Cancers

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Breast cancer is among the most common malignancies in women. From the molecular point of view, breast cancer can be grouped into different categories, including the luminal (estrogen receptor positive (ER+)) and triple negative subtypes, which show distinctive features and, thus, are sensitive to different therapies. Breast cancer cells are strongly dependent on Ca2+ influx. Store-operated Ca2+ entry (SOCE) has been found to support a variety of cancer hallmarks including cell viability, proliferation, migration, and metastasis. The Ca2+ channels of the Orai family and the endoplasmic reticulum Ca2+ sensor STIM1 are the essential components of SOCE, but the extent of Ca2+ influx is fine-tuned by several regulatory proteins, such as the STIM1 modulators SARAF and EFHB. Here, we show that the expression and/or function of SARAF and EFHB is altered in breast cancer cells and both proteins are required for cell proliferation, migration, and viability. EFHB expression is upregulated in luminal and triple negative breast cancer (TNBC) cells and is essential for full SOCE in these cells. SARAF expression was found to be similar in breast cancer and pre-neoplastic breast epithelial cells, and SARAF knockdown was found to result in enhanced SOCE in pre-neoplastic and TNBC cells. Interestingly, silencing SARAF expression in ER+ MCF7 cells led to attenuation of SOCE, thus suggesting a distinctive role for SARAF in this cell type. Finally, we used a combination of approaches to show that molecular knockdown of SARAF and EFHB significantly attenuates the ability of breast cancer cells to proliferate and migrate, as well as cell viability. In aggregate, SARAF and EFHB are required for the fine modulation of SOCE in breast cancer cells and play an important role in the maintenance of proliferation, migration, and viability in these cells.

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Functional role of TRPC6 and STIM2 in cytosolic and endoplasmic reticulum Ca2+ content in resting estrogen receptor-positive breast cancer cells

Cited by 13 publications

References 31 publications

Furin Prodomain ppFurin Enhances Ca2+ Entry Through Orai and TRPC6 Channels’ Activation in Breast Cancer Cells

Furin Prodomain ppFurin Enhances Ca2+ Entry Through Orai and TRPC6 Channels’ Activation in Breast Cancer Cells

TRPM4 in Cancer—A New Potential Drug Target

SARAF and EFHB Modulate Store-Operated Ca2+ Entry and Are Required for Cell Proliferation, Migration and Viability in Breast Cancer Cells

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