Store-Operated Ca2+ Entry in Tumor Progression: From Molecular Mechanisms to Clinical Implications

Chen, Yih-Fung; Lin, Peng; Yeh, Yu Min; Chen, Li Hsien; Shen, Meng‐Ru

doi:10.3390/cancers11070899

Cited by 53 publications

(47 citation statements)

References 150 publications

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“…Ca 2+ signaling is critical in regulating focal adhesion dynamics [21], and SOCE upregulation results in cancer cell migration, invasion, and metastasis [59]. In this study, we demonstrated not only the upregulation of SOCE but also that of SOCE-related SOC channels, such as TRPC1, Orai1, and Orai2 (Fig.…”

Section: Discussionsupporting

confidence: 51%

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions

et al. 2020

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Background: Among gynecological cancers, ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer. Therefore, novel strategies are required to improve its poor prognosis. Formation and disassembly of focal adhesions are regulated dynamically during cell migration, which plays an essential role in cancer metastasis. Metastasis is intricately linked with resistance to chemotherapy, but the molecular basis for this link is unknown. Methods: Transwell migration and wound healing migration assays were used to analyze the migration ability of ovarian cancer cells. Real-time recordings by total internal reflection fluorescence microscope (TIRFM) were performed to assess the turnover of focal adhesions with fluorescence protein-tagged focal adhesion molecules. SOCE inhibitors were used to verify the effects of SOCE on focal adhesion dynamics, cell migration, and chemoresistance in chemoresistant cells. Results: We found that mesenchymal-like chemoresistant IGROV1 ovarian cancer cells have higher migration properties because of their rapid regulation of focal adhesion dynamics through FAK, paxillin, vinculin, and talin. Focal adhesions in chemoresistant cells, they were smaller and exhibited strong adhesive force, which caused the cells to migrate rapidly. Store-operated Ca 2+ entry (SOCE) regulates focal adhesion turnover, and cell polarization and migration. Herein, we compared SOCE upregulation in chemoresistant ovarian cancer cells to its parental cells. SOCE inhibitors attenuated the assembly and disassembly of focal adhesions significantly. Results of wound healing and transwell assays revealed that SOCE inhibitors decreased chemoresistant cell migration. Additionally, SOCE inhibitors combined with chemotherapeutic drugs could reverse ovarian cancer drug resistance. Conclusion: Our findings describe the role of SOCE in chemoresistance-mediated focal adhesion turnover, cell migration, and viability. Consequently, SOCE might be a promising therapeutic target in epithelial ovarian cancer.

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Section: Discussionsupporting

confidence: 51%

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions

et al. 2020

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“…There is increasing evidence of dysregulated Ca 2+ signaling in cancer. This evidence is based on the implication of SOCs and TRP in key hallmarks of cancer progression and as prognostic markers in several types of cancers (Prevarskaya et al, 2007;Shapovalov et al, 2016;Chen et al, 2019). Some members of SOCs and TRP have been studied in PDAC, even though knowledge is less pronounced compared to other types of cancer, such as breast-, cervical-, and colorectal cancer (Chen et al, 2019).…”

Section: Orai and Stimmentioning

confidence: 99%

“…The complex of ORAI1 and STIM1 has been shown to play a role in carcinogenesis and to be involved in regulation of proliferation, migration, invasion and apoptosis in different types of cancer (Chen et al, 2019). Only two studies have been performed on PDAC showing that ORAI1 and STIM1 mediate SOC entry and that they are involved in proliferation, survival and apoptosis (Kondratska et al, 2014;Khan et al, 2020).…”

Section: Orai and Stimmentioning

confidence: 99%

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancerrelated deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

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“…8). The role of SOCE in cell migration was intensively studied in cancer cells (reviewed in 48 ), where intracellular Ca 2+ influx through STIM-Orai interaction affects focal adhesion turnover as a critical step in the migration mechanism 49 . A similar mechanism may be important in migration of pmLF and needs to be further analyzed.…”

Section: Discussionmentioning

confidence: 99%

Store-operated Ca2+ entry in primary murine lung fibroblasts is independent of classical transient receptor potential (TRPC) channels and contributes to cell migration

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Gudermann

et al. 2020

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Stromal interaction molecules (STIM1, 2) are acting as sensors for Ca 2+ in intracellular stores and activate Orai channels at the plasma membrane for store-operated Ca 2+ entry (SOCE), while classical transient receptor potential (TRPC) channel mediate receptor-operated Ca 2+ entry (Roce). Several reports, however, indicate a role for TRPC in SOCE in certain cell types. Here, we analyzed Ca 2+ influx and cell function in TRPC1/6-deficient (TRPC1/6 −/− ) and STIM1/2-deficient (STIM1/2 ΔpmLf ) primary murine lung fibroblasts (pmLF). As expected, SOCE was decreased in STIM1/2-deficient pmLF and ROCE was decreased in TRPC1/6 −/− pmLF compared to control cells. By contrast, SOCE was not significantly different in TRPC1/6 −/− pmLF and ROCE was similar in STIM1/2-deficient pmLF compared to Wt cells. Most interestingly, cell proliferation, migration and nuclear localization of nuclear factor of activated T-cells (NFATc1 and c3) were decreased after ablation of STIM1/2 proteins in pmLF. In conclusion, TRPC1/6 channels are not involved in SOCE and STIM1/2 deficiency resulted in decreased cell proliferation and migration in pmLf.Store-operated Ca 2+ entry (SOCE) also named capacitive Ca 2+ entry (CCE) was first described by J.W. Putney Jr. more than 30 years ago as depletion of intracellular Ca 2+ stores which induces the opening of plasma membrane (PM) Ca 2+ channels 1 . Since then, candidate proteins like classical transient receptor potential (TRPC) channels 2 and mechanisms, e.g. coupling of TRPC proteins to inositol 1-4-5 trisphosphate (IP3) receptor channels in the endoplasmic reticulum 3,4 for SOCE, were intensively discussed in the scientific community. In 2005 however, stromal interaction molecules (Stim in Drosophila and STIM1, STIM2 in humans) were identified as Ca 2+ sensors in the ER directly regulating SOCE in two different large-scale screening approaches 5,6 . One year later, Ca 2+ selective channels at the plasma membrane (Orai) were discovered 7-9 , which were responsible for Ca 2+ release activated Ca 2+ (CRAC) currents originally described in mast cells 10 . A molecular model was developed to support the concept that upon ER Ca 2+ depletion STIM proteins homo-multimerize and translocate to ER-PM junctions 11,12 , where they recruit and gate Orai channels via direct interaction 13 . Ca 2+ influx through Orai channels is important for cellular remodeling, e.g. in cardiovascular diseases 14 , and mutations in these channels are responsible for multiple channelopathies 15 . Irrespective of these events, TRP channels trigger Ca 2+ influx in response to extracellular stimuli or receptor activation (receptor-operated Ca 2+ influx, ROCE) independently of STIM and Orai 16 . Some labs, however, reported that TRPC channels also interact with STIM proteins 17 and/or Orai channels 18 . Along these lines, TRPC channels like TRPC1 were invoked in SOCE in certain cells of salivary glands 19 and pancreatic acini 20 , while in vascular smooth muscle cells TRPC1 channels work independently of SOCE 21 . The role of TRPC1 i...

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Store-Operated Ca2+ Entry in Tumor Progression: From Molecular Mechanisms to Clinical Implications

Cited by 53 publications

References 150 publications

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

Store-operated Ca2+ entry in primary murine lung fibroblasts is independent of classical transient receptor potential (TRPC) channels and contributes to cell migration

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