Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer

Liang, Xiubo; Zhang, Ningxia; Pan, Hongming; Xie, Jiaxin; Han, Weidong

doi:10.3389/fphar.2021.688244

Cited by 22 publications

(15 citation statements)

References 181 publications

(196 reference statements)

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“…Ion channel disorder appeared to be responsible for the enhanced migration of cancer cells and ECM dysregulation [ 30 , 31 ]. Aberrant activation of Ca 2+ -permeable channels on the endoplasmic reticulum membrane and plasma membrane led to impulse Ca 2+ influx [ 32 ]. The oscillatory Ca 2+ signaling facilitated invadopodial precursor assembly via Src activation and increased proteolytic activity of invadopodia by recruitment of ECM-degrading membrane type 1 matrix metalloproteinase (MT1-MMP) [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Zong

et al. 2022

J Ovarian Res

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Background Metastasis was the major cause of the high mortality in ovarian cancer. Although some mechanisms of metastasis in ovarian cancer were proposed, few have been targeted in the clinical practice. In the study, we aimed to identify novel genes contributing to metastasis and poor clinical outcome in ovarian cancer from bioinformatics databases. Methods Studies collecting matched primary tumors and metastases from ovarian cancer patients were searched in the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened by software R language. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the DEGs were implemented by Metascape. Venn diagram was plotted to present overlapping DEGs. The associations between the overlapping DEGs and prognosis were tested by Cox proportional hazard regression model using a cohort of ovarian cancer patients from the TCGA database. Genes affecting patients’ outcomes significantly were served as hub genes. The mechanisms of the hub genes in promoting ovarian cancer metastasis were then predicted by R software. Results Two gene expression profiles (GSE30587 and GSE73168) met the inclusion criteria and were finally analyzed. A total of 259 genes were significantly differentially expressed in GSE30587, whereas 712 genes were in GSE73168. In GSE30587, DEGs were mainly involved in extracellular matrix (ECM) organization; For GSE73168, most of DEGs showed ion trans-membrane transport activity. There were 9 overlapping genes between the two datasets (RUNX2, FABP4, CLDN20, SVEP1, FAM169A, PGM5, ZFHX4, DCN and TAS2R50). ZFHX4 was proved to be an independent adverse prognostic factor for ovarian cancer patients (HR = 1.44, 95%CI: 1.13–1.83, p = 0.003). Mechanistically, ZFHX4 was positively significantly correlated with epithelial-mesenchymal transition (EMT) markers (r = 0.54, p = 2.59 × 10−29) and ECM-related genes (r = 0.52, p = 2.86 × 10−27). Conclusions ZFHX4 might promote metastasis in ovarian cancer by regulating EMT and reprogramming ECM. For clinical applications, ZFHX4 was expected to be a prognostic biomarker for ovarian cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Zong

et al. 2022

J Ovarian Res

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“…Because of the large number of TNBCs that have an activated PI3K/AKT pathway, it is unsurprising that early phase clinical trials of both PI3K inhibitors such as buparlisib [131,132] and AKT inhibitors such as capivasertib [133] and ipatasertib [134] have been conducted in this setting. Interestingly, these trials have reported clinical activity and benefits to patients.…”

Section: The Role That Calcium Plays On the Impact Of Tp53 Mutations ...mentioning

confidence: 99%

“…The role of calcium channels in mediating therapy resistance through interplay with genomic alternations in TNBC highlights calcium channels as potential targets for personalized medicine approaches. The study of calcium channel blockers (CCBs) is an area of intense research [ 26 - 28 , 135 ] . Several calcium blocking drugs have been developed which can modulate calcium channels and be exploited as cancer treatments [ 27 , 43 , 135 , 136 ] .…”

Section: Introductionmentioning

confidence: 99%

“…The study of calcium channel blockers (CCBs) is an area of intense research [ 26 - 28 , 135 ] . Several calcium blocking drugs have been developed which can modulate calcium channels and be exploited as cancer treatments [ 27 , 43 , 135 , 136 ] . Calcium channels provide a plethora of targets to modulate Ca i 2+ , and ion channel targeting drugs are currently the second largest group of FDA-approved drugs, therefore providing a bank of new drugs which can be repurposed for the treatment of cancer [ 137 ] .…”

Section: Introductionmentioning

confidence: 99%

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Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer

Eustace¹,

Lee²,

Colley³

et al. 2022

Cancer Drug Resist

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Triple-negative breast cancer (TNBC) is characterized as an aggressive form of breast cancer (BC) associated with poor patient outcomes. For the majority of patients, there is a lack of approved targeted therapies. Therefore, chemotherapy remains a key treatment option for these patients, but significant issues around acquired resistance limit its efficacy. Thus, TNBC has an unmet need for new targeted personalized medicine approaches. Calcium (Ca2+) is a ubiquitous second messenger that is known to control a range of key cellular processes by mediating signalling transduction and gene transcription. Changes in Ca2+ through altered calcium channel expression or activity are known to promote tumorigenesis and treatment resistance in a range of cancers including BC. Emerging evidence shows that this is mediated by Ca2+, modulation supporting the function of tumour suppressor genes (TSGs) and oncogenes. This review provides insight into the underlying alterations in calcium signalling and how it plays a key role in promoting disease progression and therapy resistance in TNBC which harbours mutations in tumour protein p53 (TP53) and the PI3K/AKT pathway.

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“…Given the importance of SOCE tumor biology and cancer progression, it is plausible to suggest that the blockade of STIM1/Orai1-dependent Ca 2+ signaling can be a practical therapeutic approach for cervical cancer. Studies on preclinical animal models have demonstrated the potentials of several small-molecule SOCE inhibitors in cancer therapies [ 194 , 195 , 196 , 197 , 198 ]. However, these SOCE inhibitors have not been approved for clinical use for cancer therapies.…”

Section: Intracellular Ca 2+ Homeostasis and Store-operated Ca 2+ Entry (Soce)mentioning

confidence: 99%

The Important Role of Ion Transport System in Cervical Cancer

Chen

Shen

2021

IJMS

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Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl− channels and K+-Cl− cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca2+ homeostasis, the Ca2+ store sensor STIM molecules and plasma membrane Ca2+ channel Orai proteins, the predominant Ca2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.

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Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer

Cited by 22 publications

References 181 publications

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer

The Important Role of Ion Transport System in Cervical Cancer

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