title: The Hedgehog receptor patched functions in multidrug transport and chemotherapy resistance.
abstract: Most anticancer drugs fail to eradicate tumors, leading to the development of drug resistance and disease recurrence. The Hedgehog signaling plays a crucial role during embryonic development, but is also involved in cancer development, progression, and metastasis. The Hedgehog receptor Patched (Ptc) is a Hedgehog signaling target gene that is overexpressed in many cancer cells. Here, we show a link between Ptc and resistance to chemotherapy, and provide new insight into Ptc function. Ptc is cleared from the plasma membrane upon interaction with its ligand Hedgehog, or upon treatment of cells with the Hedgehog signaling antagonist cyclopamine. In both cases, after incubation of cells with doxorubicin, a chemotherapeutic agent that is used for the clinical management of recurrent cancers, we observed an inhibition of the efflux of doxorubicin from Hedgehog-responding fibroblasts, and an increase of doxorubicin accumulation in two different cancer cell lines that are known to express aberrant levels of Hedgehog signaling components. Using heterologous expression system, we stringently showed that the expression of human Ptc conferred resistance to growth inhibition by several drugs from which chemotherapeutic agents such as doxorubicin, methotrexate, temozolomide, and 5-fluorouracil. Resistance to doxorubicin correlated with Ptc function, as shown using mutations from Gorlin's syndrome patients in which the Ptc-mediated effect on Hedgehog signaling is lost. Our results show that Ptc is involved in drug efflux and multidrug resistance, and suggest that Ptc contributes to chemotherapy resistance of cancer cells.
authors: Université Nice Sophia Antipolis, CNRS-UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Valbonne, France.
authors: Michel
authors: M
authors: Bidet
authors: Amandine
authors: A
authors: Tomico
authors: Patrick
authors: P
authors: Martin
authors: Hélène
authors: H
authors: Guizouarn
authors: Patrick
authors: P
authors: Mollat
authors: Isabelle
authors: I
authors: Mus-Veteau
mesh_terms: D000167:Acriflavine / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D004317:Doxorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014981:Xenopus
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000167:Acriflavine; D004317:Doxorubicin