title: The cystine/glutamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain.
abstract: Bone is one of the leading sites of metastasis for frequently diagnosed malignancies, including those arising in the breast, prostate and lung. Although these cancers develop unnoticed and are painless in their primary sites, bone metastases result in debilitating pain. Deeper investigation of this pain may reveal etiology and lead to early cancer detection. Cancer-induced bone pain (CIBP) is inadequately managed with current standard-of-care analgesics and dramatically diminishes patient quality of life. While CIBP etiology is multifaceted, elevated levels of glutamate, an excitatory neurotransmitter, in the bone-tumor microenvironment may drive maladaptive nociceptive signaling. Here, we establish a relationship between the reactive nitrogen species peroxynitrite, tumor-derived glutamate, and CIBP. In vitro and in a syngeneic in vivo model of breast CIBP, murine mammary adenocarcinoma cells significantly elevated glutamate via the cystine/glutamate antiporter system xc. The well-known system xc inhibitor sulfasalazine significantly reduced levels of glutamate and attenuated CIBP-associated flinching and guarding behaviors. Peroxynitrite, a highly reactive species produced in tumors, significantly increased system xc functional expression and tumor cell glutamate release. Scavenging peroxynitrite with the iron and mangano-based porphyrins, FeTMPyP and SRI10, significantly diminished tumor cell system xc functional expression, reduced femur glutamate levels and mitigated CIBP. In sum, we demonstrate how breast cancer bone metastases upregulate a cystine/glutamate co-transporter to elevate extracellular glutamate. Pharmacological manipulation of peroxynitrite or system xc attenuates CIBP, supporting a role for tumor-derived glutamate in CIBP and validating the targeting of system xc as a novel therapeutic strategy for the management of metastatic bone pain.
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Slosky
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Neemah M
authors.initials: NM
authors.lastname: BassiriRad
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Symons
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Thompson
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Doyle
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Forte
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Staatz
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Bui
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
authors.affiliation: Department of Pharmacology & Physiology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Tally M
authors.initials: TM
authors.lastname: Largent-Milnes
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
mesh_terms: D000230:Adenocarcinoma / Q000150:complications* / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017920:Antiporters / Q000494:pharmacology; D001859:Bone Neoplasms / Q000150:complications* / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000556:secondary; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000072716:Cancer Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D064593:Heterografts; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D030421:Peroxynitrous Acid / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C492721:5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato-iron(III); D000894:Anti-Inflammatory Agents, Non-Steroidal; D017920:Antiporters; D002135:Calcium-Binding Proteins; D008665:Metalloporphyrins; C503114:Sri protein, mouse; D030421:Peroxynitrous Acid; D018698:Glutamic Acid; D012460:Sulfasalazine