title: ABCG2 is required to control the sonic hedgehog pathway in side population cells with stem-like properties.
abstract: The Sonic Hedgehog (Hh) pathway has been implicated in the maintenance of stem or progenitor cells in many adult tissues. Importantly, abnormal Hh pathway activation is also associated with initiation of neoplasia, but its role in tumor growth is still unclear. Here, we demonstrate that cyclopamine, a plant-derived alkaloid product used to inhibit the Hh signaling pathway, reduces the Side Population (SP) obtained by Hoechst 33342 (Ho342) dye measurements. In addition, cyclopamine is able to modulate, along with oxysterols and other products, the ABCG2 transporter by increasing Ho342 and mitoxantrone uptake. Therefore, if the SP is solely measured as a Ho342 dye extruding fraction, this may be significantly modulated by the inhibition of ABCG2 transport fraction, independently from the action of cyclopamine on the Hh pathway. Our results indicate that ABCG2 may act in the upstream regulation of the Hh signaling pathway to protect the stemness of the SP compartment, giving support to the cancer stem cell hypothesis and suggesting that ABCG2 is not only critical for increased resistance to anticancer agents.
authors.affiliation: Brain Tumor Biology Unit, CIFA, University of Navarra School of Sciences, Pamplona, Spain.
authors.forename: Jana
authors.initials: J
authors.lastname: Balbuena
authors.forename: Gisela
authors.initials: G
authors.lastname: Pachon
authors.forename: Guillermo
authors.initials: G
authors.lastname: Lopez-Torrents
authors.forename: Josep M
authors.initials: JM
authors.lastname: Aran
authors.forename: Javier S
authors.initials: JS
authors.lastname: Castresana
authors.forename: Jordi
authors.initials: J
authors.lastname: Petriz
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001562:Benzimidazoles / Q000032:analysis; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology; D007624:KB Cells; D008942:Mitoxantrone / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014704:Veratrum Alkaloids / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D002227:Carbazoles; D053823:Hedgehog Proteins; D006888:Hydroxycholesterols; D026121:Indole Alkaloids; D009363:Neoplasm Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D014704:Veratrum Alkaloids; C010206:jervine; C049985:staurosporine aglycone; D008942:Mitoxantrone; C017807:bisbenzimide ethoxide trihydrochloride; C000541:cyclopamine