title: Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells.
abstract: Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.
authors: Thoracic Oncology Section, Surgery Branch, Laboratory of Pathology, Clinical Pharmacy Department, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors: Mary
authors: M
authors: Zhang
authors: Aarti
authors: A
authors: Mathur
authors: Yuwei
authors: Y
authors: Zhang
authors: Sichuan
authors: S
authors: Xi
authors: Scott
authors: S
authors: Atay
authors: Julie A
authors: JA
authors: Hong
authors: Nicole
authors: N
authors: Datrice
authors: Trevor
authors: T
authors: Upham
authors: Clinton D
authors: CD
authors: Kemp
authors: R Taylor
authors: RT
authors: Ripley
authors: Gordon
authors: G
authors: Wiegand
authors: Itzak
authors: I
authors: Avital
authors: Patricia
authors: P
authors: Fetsch
authors: Haresh
authors: H
authors: Mani
authors: Daniel
authors: D
authors: Zlott
authors: Robert
authors: R
authors: Robey
authors: Susan E
authors: SE
authors: Bates
authors: Xinmin
authors: X
authors: Li
authors: Mahadev
authors: M
authors: Rao
authors: David S
authors: DS
authors: Schrump
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008926:Plicamycin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D062789:Tobacco Products / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D012906:Smoke; D008926:Plicamycin