The calcium-sensing receptor (CaR) is responsive to changes in the extracellular Ca(2+) (Ca(2+)(o)) concentration. It is a member of the largest family of cell surface receptors, the G protein-coupled receptors, and it has been shown to be involved in Ca(2+)(o) homeostasis. Apart from its primary role in Ca(2+)(o) homeostasis, the CaR may be involved in phenomena that allow for the development of many types of benign or malignant tumors, from parathyroid adenomas to breast, prostate, and colon cancers. For example, whereas the CaR is expressed in both normal and malignant breast tissue, increased CaR levels have been reported in highly metastatic primary breast cancer cells and breast cancer cell lines, possibly contributing to their malignancy and associated alterations in their biological properties. In these settings the CaR exhibits oncogenic properties. Enhanced CaR expression and altered proliferation of prostate cancer cells in response to increased Ca(2+)(o) have also been described. In contrast, colon and parathyroid cancers often present with reduced or absent CaR expression, and activation of this receptor decreases cell proliferation, suggesting a role for the CaR as a tumor suppressor gene. Thus, the CaR may play an important role in the development of many types of neoplasia. Herein, we review the role of the CaR in various benign and malignant tumors in further detail, describing its contribution to parathyroid tumors, breast, prostate, and colon cancers, and we evaluate how pharmacological manipulations of this receptor may be of interest for the treatment of certain cancers in the future.
Introduction Human cathelicidin antimicrobial protein, hCAP18, and its C-terminal peptide LL-37 is a multifunctional protein. In addition to being important in antimicrobial defense, it induces chemotaxis, stimulates angiogenesis and promotes tissue repair. We previously showed that human breast cancer cells express high amounts of hCAP18, and hypothesised that hCAP18/LL-37 may be involved in tumour progression.
The calcium-sensing receptor (CaR) belongs to the G proteincoupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain.
BackgroundSorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking.MethodsWe used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used.ResultsWe observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival.ConclusionThese findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0526-2) contains supplementary material, which is available to authorized users.
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