title: Magnesium homeostasis in colon carcinoma LoVo cells sensitive or resistant to doxorubicin.
abstract: Neoplastic cells accumulate magnesium, an event which provides selective advantages and is frequently associated with TRPM7 overexpression. Little is known about magnesium homeostasis in drug-resistant cancer cells. Therefore, we used the colon cancer LoVo cell model and compared doxorubicin-resistant to sensitive cells. In resistant cells the concentration of total magnesium is higher while its influx capacity is lower than in sensitive cells. Accordingly, resistant cells express lower amounts of the TRPM6 and 7, both involved in magnesium transport. While decreased TRPM6 levels are due to transcriptional regulation, post-transcriptional events are involved in reducing the amounts of TRPM7. Indeed, the calpain inhibitor calpeptin markedly increases the levels of TRPM7 in resistant cells. In doxorubicin-sensitive cells, silencing TRPM7 shifts the phenotype to one more similar to resistant cells, since in these cells silencing TRPM7 significantly decreases the influx of magnesium, increases its intracellular concentration and increases resistance to doxorubicin. On the other hand, calpain inhibition upregulates TRPM7, decreases intracellular magnesium and enhances the sensitivity to doxorubicin of resistant LoVo cells. We conclude that in LoVo cells drug resistance is associated with alteration of magnesium homeostasis through modulation of TRPM7. Our data suggest that TRPM7 expression may be an additional undisclosed player in chemoresistance.
authors.affiliation: Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via G.B. Grassi 74, Milano I-20157.
authors.forename: Sara
authors.initials: S
authors.lastname: Castiglioni
authors.affiliation: Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via G.B. Grassi 74, Milano I-20157.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cazzaniga
authors.affiliation: Istituto di Patologia Generale, Facoltà di Medicina, Università Cattolica del Sacro Cuore, Largo F. Vito 1, Roma I-00168.
authors.forename: Valentina
authors.initials: V
authors.lastname: Trapani
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università Alma Mater di Bologna, Via San Donato 19/2, Bologna I-40127.
authors.forename: Concettina
authors.initials: C
authors.lastname: Cappadone
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università Alma Mater di Bologna, Via San Donato 19/2, Bologna I-40127.|Istituto Nazionale Biostrutture e Biosistemi, Viale delle Medaglie d'oro 305, Roma I-00136.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Farruggia
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università Alma Mater di Bologna, Via San Donato 19/2, Bologna I-40127.
authors.forename: Lucia
authors.initials: L
authors.lastname: Merolle
authors.affiliation: Istituto di Patologia Generale, Facoltà di Medicina, Università Cattolica del Sacro Cuore, Largo F. Vito 1, Roma I-00168.
authors.forename: Federica I
authors.initials: FI
authors.lastname: Wolf
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università Alma Mater di Bologna, Via San Donato 19/2, Bologna I-40127.|Istituto Nazionale Biostrutture e Biosistemi, Viale delle Medaglie d'oro 305, Roma I-00136.
authors.forename: Stefano
authors.initials: S
authors.lastname: Iotti
authors.affiliation: Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via G.B. Grassi 74, Milano I-20157.
authors.forename: Jeanette A M
authors.initials: JAM
authors.lastname: Maier
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D008274:Magnesium / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; C071482:calpeptin; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D002154:Calpain; D008274:Magnesium