MithramycinRepressesBasalandCigaretteSmoke-Induced ExpressionofABCG2andInhibitsStemCellSignalinginLung and Esophageal Cancer Cells

Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophagealcancers,yettheunderlyingmechanismsremainunknown.Inthisstudy,weobservedthatexposureof esophageal cancer cells tocigarette smoke condensate (CSC) ledto upregulation ofthe xenobiotic pumpABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore,CSCincreasedthesidepopulationoflungcancercellscontainingcancerstemcells.Upregulationof 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 ABCG2induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSCmediated 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. Cancer Res; 72(16); 4178–92. � 2012 AACR.