title: SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness.
abstract: The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K(+) channel human ether-à-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/β1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating cross-talk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition.
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France. Department of Physiology, University of California, San Francisco, San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Crottès
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Rapetti-Mauss
authors.affiliation: Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital "Virgen de la Arrixaca", Murcia, Spain. Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Alcaraz-Perez
authors.affiliation: Université Nice Sophia Antipolis, C3M, Inserm U1065, Nice, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Tichet
authors.affiliation: Unit of Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Gariano
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martial
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Guizouarn
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pellissier
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Loubat
authors.affiliation: Université Nice Sophia Antipolis, IPMC, CNRS UMR7275, Sophia Antipolis, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Popa
authors.affiliation: Université Nice Sophia Antipolis, IPMC, CNRS UMR7275, Sophia Antipolis, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Paquet
authors.affiliation: Unit of Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
authors.affiliation: Université Nice Sophia Antipolis, C3M, Inserm U1065, Nice, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tartare-Deckert
authors.affiliation: Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital "Virgen de la Arrixaca", Murcia, Spain. Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Cayuela
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Borgese
authors.affiliation: Université Nice Sophia Antipolis, iBV, Nice, France. CNRS, iBV, UMR7277, Nice, France. INSERM U1091, Nice, France. soriani@unice.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Soriani
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017480:Receptors, sigma / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D000097605:Sigma-1 Receptor
chemical_list: D017480:Receptors, sigma; D000097605:Sigma-1 Receptor