Hedgehog signaling regulates drug sensitivity by targeting ABC transporters ABCB1 and ABCG2 in epithelial ovarian cancer

Mol Carcinog. 2014 Aug;53(8):625-34. doi: 10.1002/mc.22015. Epub 2013 Feb 19.

Abstract

A major challenge of successful chemotherapy in ovarian cancer is overcoming intrinsic or acquired multi-drug resistance caused by active drug efflux mediated by ATP-binding cassette (ABC) transporters. Regulation of these transporters in ovarian cancer is poorly understood. We have found that abnormal expression of the hedgehog (Hh) signaling pathway transcription factor Gli1 is involved in the regulation of ABC transporters ABCB1 and ABCG2 in ovarian cancer. Hh is a known regulator of cancer cell proliferation and differentiation in several other types of invasive and metastatic malignancies. Our work has demonstrated that Gli1 is abnormally activated in a portion of ovarian cancers. Inhibition of Gli1 expression decreases ABCB1 and ABCG2 gene expression levels and enhances the response of ovarian cancer cells to certain chemotherapeutic drugs. The underlying mechanism is a direct association of Gli1 with a specific consensus sequence located in the promoter region of ABCB1 and ABCG2 genes. This study provides new understanding of ABC gene regulation by Hh signaling pathway, which may lead to the identification of new markers to detect and to anticipate ovarian cancer chemotherapy drug sensitivity.

Keywords: ABCB1; ABCG2; Gli1; hedgehog; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Carcinoma, Ovarian Epithelial
  • Cell Proliferation / drug effects
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Electrophoretic Mobility Shift Assay
  • Female
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Luciferases / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Hedgehog Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • Luciferases