Plasma membrane Ca2+-permeable channels and sodium/calcium exchangers in tumorigenesis and tumor development of the upper gastrointestinal tract

Ding, Jianhong; Jin, Zhe; Yang, Xiaoxu; Lou, Jun; Shan, Weixi; Hu, Yanxia; Du, Qian; Liao, Qiushi; Xu, Jingyu; Xie, Rui

doi:10.1016/j.canlet.2020.01.026

Cited by 15 publications

(5 citation statements)

References 79 publications

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“…Several mechanisms conferring to GC cells, a selective advantage to escape drug-induced apoptosis, have been described ( Russi et al, 2019b ). In this scenario, ion channels may play a role since they mediate several responses in cellular physiology and are often dysregulated in most types of cancer, including those of the gastrointestinal tract ( Anderson et al, 2019 ; Ding et al, 2020 ; Stokłosa et al, 2020 ). Among the different types of ion channels, those involved in the regulation of Ca 2+ flux have been found to affect the sensitivity of GC cells to apoptotic stimuli.…”

Section: Introductionmentioning

confidence: 99%

Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

et al. 2021

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Gastric cancer (GC) is characterized by poor efficacy and modest clinical impact of current therapies, in which apoptosis evasion is relevant. Intracellular calcium homeostasis dysregulation is associated with apoptosis escaping, and aberrant expression of calcium regulator genes could promote GC drug resistance. Since we previously found a prognostic value for TRPV2 calcium channel expression in GC, we aimed to characterize the role of TRPV2 in cisplatin resistance. Using the TCGA-STAD dataset, we performed a differential gene expression analysis between GC samples in upper and lower tertiles of TRPV2 expression, and then through a gene set analysis, we highlighted the enriched ontology and canonical pathways. We used qRT-PCR to assess TRPV2 expression in three GC cell lines and flow cytometry to evaluate cisplatin-induced cell death rates. Calcium green-1-AM assay was used to estimate differences in intracellular Ca2+ concentrations after inhibition of TRPV2. We engineered AGS cell line to overexpress TRPV2 and used confocal microscopy to quantify its overexpression and localization and flow cytometry to evaluate their sensitivity to cisplatin. Consistent with our hypothesis, among enriched gene sets, we found a significant number of those involved in the regulation of apoptosis. Subsequently, we found an inverse correlation between TRPV2 expression and sensitivity to cisplatin in GC cell lines. Moreover, we demonstrated that inhibition of TRPV2 activity by tranilast blocks the efflux of Ca2+ ions and, in combination with cisplatin, induced a significant increase of apoptotic cells (p = 0.004). We also demonstrated that TRPV2 exogenous expression confers a drug-resistant phenotype, and that tranilast is able to revert this phenotype, restoring cisplatin sensitivity. Our findings consistently suggested that TRPV2 could be a potential target for overcoming cisplatin resistance by promoting apoptosis. Notably, our data are a prerequisite for the potential reposition of tranilast to the treatment of GC patients and anticipate the in vivo evaluation.

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Section: Introductionmentioning

confidence: 99%

Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

et al. 2021

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“…Although the occurrence and progression of cancer are complex, numerous findings indicate that aberrant intracellular Ca 2+ ([Ca 2+ ] i ) signaling is involved in the development of several types of gastrointestinal (GI) cancers, including GC and colon cancer [4]. Since plasma membrane Ca 2+ -permeable channels play important roles in the regulation of [Ca 2+ ] i , their aberrant expression and function are positively associated with the occurrence and development of GI tumors [5,6]. Consistently, we revealed that activation of G protein-coupled receptors (GPCRs), such as Ca 2+ sensing receptors (CaSR) and vasoactive intestinal polypeptide (VIP) receptors, promotes GC progression via transient receptor potential vanilloid receptor 4 (TRPV4) channels and the Ca 2+ signaling [7,8].…”

Section: Introductionmentioning

confidence: 99%

The role of TRPV1 ion channels in the suppression of gastric cancer development

Gao

Yang

Chen

et al. 2020

J Exp Clin Cancer Res

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Background Although the aberrant expression and function of most Ca2+-permeable channels are known to promote gastrointestinal tumors, the association between transient receptor potential vanilloid receptor 1 (TRPV1) channels and gastric cancer (GC) has not yet been explored. Herein, we sought to determine the role of TRPV1 channels in the development of GC and to elucidate the underlying molecular mechanisms involved therein. Methods Immunohistochemistry, qPCR, Western blot, immunofluorescence assays were used to detect the mRNA and protein expression of TRPV1 in GC cells and tissues, and the clinical significance of TRPV1 in GC was also studied by clinicopathologic analysis. CCK8, colony formation, flow cytometry assays were used to detect the proliferation and survival of GC cells, while transwell assay was used to detect migration and invasion of GC cells in vitro. Tumor xenograft and peritoneal dissemination assays in nude mice were used to examine the role of TRPV1 in GC development in vivo. Results TRPV1 expression was significantly downregulated in human primary GC tissues compared to their adjacent tissues. The decreased expression of TRPV1 proteins in GC tissues was positively correlated with tumor size, histological grade, lymphatic metastasis, clinical stage, and was strongly correlated with poor prognosis of GC patients. Moreover, the expression of TRPV1 was closely correlated with Ki67, VEGFR, and E-cadherin, all of which are the well-known cancer markers for proliferation and metastasis. TRPV1 proteins were predominately expressed on the plasma membrane in several GC cell lines. TRPV1 overexpression blocked cell cycle at G1 phase to inhibit GC cell proliferation and attenuated migration and invasion of GC cells in vitro, but TRPV1 knockdown increased these parameters. TRPV1 significantly reduced gastric tumor size, number and peritoneal dissemination in vivo. Mechanistically, TRPV1 overexpression in GC cells increased [Ca2+]i, activated CaMKKβ and AMPK phosphorylation, and decreased expression of cyclin D1 and MMP2, while TRPV1 knockdown induced the opposite effects. Conclusions TRPV1 uniquely suppresses GC development through a novel Ca2+/CaMKKβ/AMPK pathway and its downregulation is correlated with poor survival of human GC patients. Thus, TRPV1 upregulation and its downstream signaling may represent a promising target for GC prevention and therapy.

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“…The 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, potentiated calcium signaling via the reverse mode NCX. NNK supported proliferation and migration of human ESCC cells induced by NCX1 activation [ 27 ]. Xu et al [ 28 ] have shown that the interaction among NHE1, NCX1, and calmodulin (CaM) regulates proliferation mediated by IL6 (a pro-inflammatory cytokine), migration, and invasion of human hepatocellular carcinoma (HCC) cells.…”

Section: Ncx1 In Solid Tumorsmentioning

confidence: 99%

“…In human HCC, the TRPC6/NCX1 (canonical transient receptor potential channel 6 and NCX1) complex promotes the effect of TGF-β on cell migration, invasion, and metastasis formation [ 30 ]. Formation of the TRPC6/NCX1 molecular complex is currently being studied for TGF-β-stimulated ([Ca 2+ ] cyt ) signaling in HCC cells [ 27 ]. In pancreatic cancer cells, TGF-β also induces entry of Ca 2+ via TRPC1 and NCX1 and increases cytosolic levels of Ca 2+ .…”

Section: Ncx1 In Solid Tumorsmentioning

confidence: 99%

Role of Sodium/Calcium Exchangers in Tumors

et al. 2020

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The sodium/calcium exchanger (NCX) is a unique calcium transport system, generally transporting calcium ions out of the cell in exchange for sodium ions. Nevertheless, under special conditions this transporter can also work in a reverse mode, in which direction of the ion transport is inverted—calcium ions are transported inside the cell and sodium ions are transported out of the cell. To date, three isoforms of the NCX have been identified and characterized in humans. Majority of information about the NCX function comes from isoform 1 (NCX1). Although knowledge about NCX function has evolved rapidly in recent years, little is known about these transport systems in cancer cells. This review aims to summarize current knowledge about NCX functions in individual types of cancer cells.

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Plasma membrane Ca2+-permeable channels and sodium/calcium exchangers in tumorigenesis and tumor development of the upper gastrointestinal tract

Cited by 15 publications

References 79 publications

Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

The role of TRPV1 ion channels in the suppression of gastric cancer development

Role of Sodium/Calcium Exchangers in Tumors

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