Mithramycin Represses Basal and Cigarette Smoke―Induced Expression of ABCG2 and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-08, Vol.72 (16), p.4178-4192
• Main Authors: ZHANG, Mary, MATHUR, Aarti, WIEGAND, Gordon, AVITAL, Itzak, FETSCH, Patricia, MANI, Haresh, ZLOTT, Daniel, ROBEY, Robert, BATES, Susan E, XINMIN LI, RAO, Mahadev, SCHRUMP, David S, YUWEI ZHANG, SICHUAN XI, ATAY, Scott, HONG, Julie A, DATRICE, Nicole, UPHAM, Trevor, KEMP, Clinton D, RIPLEY, R. Taylor
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - etiology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - biosynthesis; Biological and medical sciences; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - etiology; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - etiology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Nude; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Pharmacology. Drug treatments; Plicamycin - pharmacology; Pneumology; Signal Transduction - drug effects; Smoke - adverse effects; Tobacco Products - toxicity; Tobacco, tobacco smoking; Toxicology; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-3983

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.