Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells

Mary Zhang, Aarti Mathur, Yuwei Zhang, Sichuan Xi, Scott Atay, Julie A. Hong, Nicole Datrice, Trevor Upham, Clinton D. Kemp, R. Taylor Ripley, Gordon Wiegand, Itzak Avital, Patricia Fetsch, Haresh Mani, Daniel Zlott, Robert Robey, Susan E. Bates, Xinmin Li, Mahadev Rao, David S. Schrump

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53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4178-4192
Number of pages15
JournalCancer Research
Volume72
Issue number16
DOIs
Publication statusPublished - 15-08-2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Zhang, M., Mathur, A., Zhang, Y., Xi, S., Atay, S., Hong, J. A., Datrice, N., Upham, T., Kemp, C. D., Ripley, R. T., Wiegand, G., Avital, I., Fetsch, P., Mani, H., Zlott, D., Robey, R., Bates, S. E., Li, X., Rao, M., & Schrump, D. S. (2012). Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells. Cancer Research, 72(16), 4178-4192. https://doi.org/10.1158/0008-5472.CAN-11-3983