The expression and functional characterization of sigma (σ) 1 receptors in breast cancer cell lines

Aydar, Ebru; Uysal-Onganer, Pinar; Perrett, Rebecca; Djamgoz, Mustafa B.A.; Palmer, Christopher P.

doi:10.1016/j.canlet.2005.11.011

Cited by 107 publications

(119 citation statements)

References 17 publications

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“…Sigma-1 receptors are known as tumor markers (11,13,41), but the function of these enigmatic proteins in cancer cells has not been clearly described yet. The aim of the present study was …”

Section: Discussionmentioning

confidence: 99%

“…The sigma-1 receptors are expressed in various tissues including the brain, the pituitary, and the liver (2, 8 -10). Surprisingly, very high levels of sigma receptors have been detected in tumor cells when compared with normal cells (11,12). Indeed, the expression of sigma receptors in cancer biopsies is correlated with the proliferating state of the cells so that these proteins are now commonly considered to be tumor biomarkers (13,14).…”

mentioning

confidence: 99%

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Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl– Channels

Renaudo¹,

L’Hoste²,

Guizouarn

et al. 2007

Journal of Biological Chemistry

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The sigma-1 receptor is an intracellular protein characterized as a tumor biomarker whose function remains mysterious. We demonstrate herein for the first time that highly selective sigma ligands inhibit volume-regulated chloride channels (VRCC) in small cell lung cancer and T-leukemia cells. Sigma ligands and VRCC blockers provoked a cell cycle arrest underlined by p27 accumulation. In stably sigma-1 receptor-transfected HEK cells, the proliferation rate was significantly lowered by sigma ligands when compared with control cells. Sigma ligands produced a strong inhibition of VRCC in HEK-transfected cells but not in control HEK. Surprisingly, the activation rate of VRCC was dramatically delayed in HEK-transfected cells in the absence of ligands, indicating that sigma-1 receptors per se modulate cell regulating volume processes in physiological conditions. Volume measurements in hypotonic conditions revealed indeed that the regulatory volume decrease was delayed in HEK-transfected cells and virtually abolished in the presence of igmesine in both HEK-tranfected and T-leukemic cells. Moreover, HEKtransfected cells showed a significant resistance to staurosporine-induced apoptosis volume decrease, indicating that sigma-1 receptors protect cancer cells from apoptosis. Altogether, our results show for the first time that sigma-1 receptors modulate "cell destiny" through VRCC and cell volume regulation.Sigma receptors are intracellular proteins that were first postulated as opioid receptors on the basis of pharmacological and behavioral studies (1). Finally, 20 years of pharmacological studies and the cloning of the sigma-1 receptor subtype in 1996 revealed indeed that the "sigma-binding site" corresponded to a 24-kDa protein unrelated to other mammalian proteins and localized in the inner face of the plasma membrane and the membranes of the endoplasmic reticulum and the nucleus (2-5). Although high concentrations of neurosteroids have been shown to interact with brain sigma-1 receptors in behavioral studies (for review see Ref. 6), no high affinity endogene sigma ligand has been identified yet. Nonetheless, exogene compounds from disparate chemical classes ((ϩ)-benzomorphans, cocaine, guanidines, and neuroleptics for example) have been characterized or developed as highly selective sigma ligands (7). The sigma-1 receptors are expressed in various tissues including the brain, the pituitary, and the liver (2, 8 -10). Surprisingly, very high levels of sigma receptors have been detected in tumor cells when compared with normal cells (11,12). Indeed, the expression of sigma receptors in cancer biopsies is correlated with the proliferating state of the cells so that these proteins are now commonly considered to be tumor biomarkers (13,14). Consequently, many sigma ligands are developed nowadays for imagery (positon emission tomography scan) to detect early stage tumors (15, 16). However, if sigma receptors represent exciting targets to detect cancers in vivo, very few data are available on both the function and the action m...

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“…Sigma-1 receptors are known as tumor markers (11,13,41), but the function of these enigmatic proteins in cancer cells has not been clearly described yet. The aim of the present study was …”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl– Channels

Renaudo¹,

L’Hoste²,

Guizouarn

et al. 2007

Journal of Biological Chemistry

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“…To confirm by independent means that PLCg1 knockdown impairs adhesion, 'single cell adhesion measurement apparatus' (Aydar et al, 2006) was used. In this system, cell adhesive strength is monitored indirectly by measuring the force required to detach cells from their substratum.…”

Section: Plcg1 Knockdown Impairs Adhesion and Motility-related Procesmentioning

confidence: 99%

Phospholipase Cγ1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion

et al. 2007

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Phospholipase Cc1 (PLCc1) is activated downstream of a variety of extracellular stimuli and has previously been implicated in the regulation of motility responses central to tumour cell invasion. In this study, we used a novel RNAi vector system to achieve conditional PLCc1 knockdown in PC3LN3 human prostate carcinoma cells for further evaluation of PLCc1 in tumour cell biology. Using this approach, we revealed a role for PLCc1 in the regulation of PC3LN3 cell adhesion that appears to be independent of its effects on tumour cell chemotactic migration and spreading in response to extracellular matrix. Subsequent microarray analysis of PLCc1-knockdown cells revealed Rap GEF1 mRNA to be decreased in response to PLCc1 loss. This translated into a decrease in Rap GEF1 protein levels and a significant loss of Rap1 activity in PLCc1-knockdown cells. Transient knockdown of Rap GEF1 caused a reduction in PC3LN3 adhesion while overexpression of Rap GEF1 rescued the PLCc1 knockdown-induced adhesion defect. These data highlight control of the Rap GEF1-Rap1 molecular switch as a specific requirement for PLCc1-mediated tumour cell adhesion.

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“…The dose dependence was consistent with the VGSC being TTX resistant, as would be expected for nNa v 1.5 ). Previously we demonstrated that the non-metastatic BCa cell line (MCF10A) expressed a lower amount of sigma-1 receptor when compared to the metastatic cell line MDA-MB-231 (Aydar et al 2006). …”

Section: Initial Characterisationmentioning

confidence: 97%

“…The role that sigma-1 receptors play in cancer is not clear, although it is frequently up-regulated in human cancer cells and tissues (Aydar et al 2004(Aydar et al , 2006. The most in-depth study on the role that sigma-1 receptors play in BCa was performed by Palmer et al (2007).…”

mentioning

confidence: 99%

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

et al. 2016

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co-immunoprecipitation experiments. Furthermore, application of sigma-1 drugs to the cells reduced the surface expression of nNa v 1.5 protein, which could explain how sigma-1 receptor activation could alter the metastatic behaviour of breast cancer cells. Overall, these results are consistent with the idea of a sigma-1 protein behaving like either a "chaperone" or a regulatory subunit associated with nNa v 1.5.

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The expression and functional characterization of sigma (σ) 1 receptors in breast cancer cell lines

Cited by 107 publications

References 17 publications

Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl– Channels

Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl– Channels

Phospholipase Cγ1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

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