Intercellular communication mediated by the extracellular calcium-sensing receptor

Hofer, Aldebaran M.; Curci, Silvana; Doble, Marc A.; Brown, Edward M.; Soybel, David I.

doi:10.1038/35017020

Cited by 131 publications

(98 citation statements)

References 45 publications

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“…In almost all known cases Ca 2+ signaling is initiated by extracellular events or stimuli (Riccardi, 1999;Hofer et al, 2000) in communication with cell's plasma membrane. In a recent study, however, we showed that genetic or metabolic stress, specifically affecting mitochondrial Dc m , results in the activation of a novel type of Ca 2+ signaling in C2C12 myocytes.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Amuthan

Biswas

Ananadatheerthavarada

et al. 2002

Oncogene

228

271

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We have investigated mechanisms of mitochondrial stressinduced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca 2+ ] c , and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFb1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X L were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFb1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondriato-nucleus signaling pathway operating through increased [Ca 2+ ] c plays an important role in cancer progression and metastasis. Oncogene (2002Oncogene ( ) 21, 7839 -7849. doi:10.1038 Keywords: mitochondria; calcium signaling; cathepsin L; TGFb; tumor invasion; MAP kinases IntroductionThe role of mitochondria in carcinogenesis was initially suggested by Warburg et al. (1926;Warburg, 1956), based on the observation that number of experimentally induced rodent tumors exhibit reduced respiration-coupled oxidative metabolism and increased glycolysis. Since then, altered mitochondrial morphology, as well as changes in mitochondrial enzyme patterns and membrane transport systems, have been described in several tumor types (Zafar et al., 1982). Cell fusion studies (Jonasson et al., 1977;Howell and Sager, 1978;Giguere and Morais, 1981) also suggest that unknown cytoplasmic elements may play roles in carcinogenesis. Fusion between normal cytoplasm and karyoplasts from malignant phenotypes resulted in the ablation of tumorigenicity (Israel and Schaeffer, 1987) and conversely, the cytoplasm of the malignant phenotype could transfer the malignancy to the karyoplasts from normal cells (Israel and Schaeffer, 1988). Studies using mitochondrial DNA (mtDNA)-depleted tumor cells to evaluate the role of mtDNA, and thus mitochondrial function in tumorigenicity have yielded mixed results (Giguere and Morais, 1981;Morais et al., 1994;Cavalli et al., 1997;Cavalli and Liang, 1998;Hofhaus and Gattermann, 1999). Cavalli et al. (1997) found diminished tumor formation by glioblastoma cells following depletion of mtDNA (r 0 cells) with ethidium bromide treatment, while Morais et al. (1994) found increased capacity to p...

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Section: Discussionmentioning

confidence: 99%

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Amuthan

Biswas

Ananadatheerthavarada

et al. 2002

Oncogene

228

271

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“…Moreover, treatment of monocytes with the p38 MAPK inhibitor SB203580 increased ERK1/2 activation, and this phosphorylation was blocked by the MEK inhibitor PD98059, indicating that there is also cross-talk between ERK1/2 and p38 MAPK in monocytes (42). Changes in extracellular calcium are monitored by the ubiquitously expressed extracellular calcium-sensing receptor (CaR) (43,44). Calcium-or agonist-induced activation of this G protein-coupled receptor has been linked to activation of various MAP kinases, including ERK1/2 (45)(46)(47).…”

Section: P38 Mapk Negatively Regulates Mmp-9 In Oral Cancermentioning

confidence: 99%

Calcium-induced Matrix Metalloproteinase 9 Gene Expression Is Differentially Regulated by ERK1/2 and p38 MAPK in Oral Keratinocytes and Oral Squamous Cell Carcinoma

Mukhopadhyay

Munshi

Kambhampati³

et al. 2004

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) play an important role in the invasive behavior of a number of cancers including oral squamous cell cancer (OSCC), and increased expression of MMP-9 is correlated with invasive and metastatic OSCC. Because calcium is an important regulator of keratinocyte function, the effect of modulating extracellular calcium on MMP-9 expression in OSCC cell lines was evaluated. Increasing extracellular calcium induced a dose-dependent increase in MMP-9 expression in immortalized normal and premalignant oral keratinocytes, but not in two highly invasive OSCC cell lines. Differential activation of MAPK signaling was also induced by calcium. p38 MAPK activity was downregulated, whereas ERK1/2 activity was enhanced. Pharmacologic inhibition of p38 MAPK activity or expression of a catalytically inactive mutant of the upstream kinase MAPK kinase 3 (MKK3) increased the calcium induced MMP-9 gene expression, demonstrating that p38 MAPK activity negatively regulated this process. Interestingly blocking p38 MAPK activity enhanced ERK1/2 phosphorylation, suggesting reciprocal regulation between the ERK1/2 and p38 MAPK pathways. Together these data support a model wherein calcium-induced MMP-9 expression is differentially regulated by the ERK1/2 and p38 MAPK pathways in oral keratinocytes, and the data suggest that a loss of this regulatory mechanism accompanies malignant transformation of the oral epithelium.Oral squamous cell carcinoma (OSCC) 1 is the most common malignancy of the oral cavity causing more deaths than any other oral disease (1, 2). Although OSCC is characterized by local, regional, and distant spread, the biochemical factors that underlie dissemination are poorly understood (1, 3). OSCC tumors demonstrate a progressive lack of basement membrane staining, more diffuse invasion, and a higher frequency of lymph node metastasis, suggesting that basement membrane loss reflects metastatic potential (4 -7). This is consistent with immunohistochemical and in situ hybridization studies of human OSCC tumors that implicate enzymes belonging to the matrix metalloproteinase (MMP) family, including MMP-9 (92-kDa gelatinase B), in basement membrane proteolysis and tissue invasion. The presence of gelatinolytic activity attributable to activated MMP-9 in OSCC biopsy specimens correlates with immunohistochemical staining of frozen sections and is enhanced in both highly invasive and metastatic cases, suggesting a correlation between MMP-9 activity and metastatic potential (8,9). Additional studies of human tumors have shown that MMP-9 is up-regulated in diffuse invasive OSCC specimens, with predominant localization to the invasive front (4, 10). At the cellular level, modulation of MMP-9 expression via phorbol ester treatment leads to enhanced invasive behavior (8 -10), whereas blocking MMP-9 expression in vivo reduces invasion in an orthotopic murine model of OSCC (11). These data support the hypothesis that MMP-9 is an important determinant of the invasive phenotype in OSCC.Oral keratinocytes express a...

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“…CASR has been reported to be widely expressed in several mammalian tissues, including tissues that are not clearly involved in Ca 2C metabolism such as brain, lens epithelial cells, pituitary gland, bone marrow, peripheral blood, breast ductal cells, pancreas, keratinocytes, ovarian surface epithelial cells, and the gastrointestinal system (reviewed by Brown et al (1993), McNeil et al (1998a), Hofer et al (2000), and Hofer & Brown (2003)). CASR localization in cells that seem to have no functional relationship with the maintenance of the whole-body Ca 2C balance has been linked to the regulation of different cellular processes, such as secretion, chemotaxis, apoptosis, cell proliferation, differentiation, and ion channel activity (for review see Hofer & Brown (2003)).…”

Section: Introductionmentioning

confidence: 99%

The extracellular calcium-sensing receptor is expressed in the cumulus–oocyte complex in mammals and modulates oocyte meiotic maturation

Santis¹,

Casavola²,

Reshkin³

et al. 2009

Reproduction

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The extracellular calcium-sensing receptor (CASR) plays an important role in cells involved in calcium (Ca 2C ) homeostasis by directly sensing changes in the extracellular Ca 2C ion concentration. We previously reported the localization and quantitative expression of CASR protein in human oocytes. In this study, we examined the expression and the functional role of CASR during oocyte meiotic maturation in a large mammal animal model, the horse. As in humans, CASR protein was found to be expressed in equine oocytes and cumulus cells. Western-blot analysis revealed a single 130 kDa band in denuded oocytes and a doublet of 130-120 kDa in cumulus cells. CASR labeling was observed by confocal microscopy in cumulus cells and in oocytes on the plasma membrane and within the cytoplasm at all examined stages of meiosis. Functionally, the CASR allosteric effector NPS R-467, in the presence of 2.92 mM external Ca 2C , increased oocyte maturation rate in a dose-dependent manner and its stimulatory effect was attenuated by pre-treatment with the CASR antagonist NPS 2390. NPS R-467 had no effect in suboptimal external Ca 2C (0.5 mM), indicating that it requires higher external Ca 2C to promote oocyte maturation. In oocytes treated with NPS R-467, CASR staining increased at the plasmalemma and was reduced in the cytosol. Moreover, NPS R-467 increased the activity of MAPK, also called ERK, in cumulus cells and oocytes. These results provide evidence of a novel signal transduction pathway modulating oocyte meiotic maturation in mammals in addition to the well-known systemic hormones.

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Intercellular communication mediated by the extracellular calcium-sensing receptor

Cited by 131 publications

References 45 publications

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Calcium-induced Matrix Metalloproteinase 9 Gene Expression Is Differentially Regulated by ERK1/2 and p38 MAPK in Oral Keratinocytes and Oral Squamous Cell Carcinoma

The extracellular calcium-sensing receptor is expressed in the cumulus–oocyte complex in mammals and modulates oocyte meiotic maturation

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