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.
Highlights
The Hedgehog (Hh) signaling pathway plays a crucial role in growth and patterning during embryonic development
We observed that treatment of yeasts with a proton motive force (PMF) disrupter such as carbonyl cyanide m-chlorophenylhydrazone (CCCP) [23] inhibited the increase of doxorubicin content in human Ptc (hPtc)-expressing yeasts supernatants, suggesting that the doxorubicin efflux enhancement related to hPtc expression required an intact PMF (Fig. 3A)
We show that the expression of the human Hh receptor Patched in Xenopus oocytes and in the yeast S. cerevisiae increased the efflux of doxorubicin, a chemotherapeutic agent used to treat recurrent cases of cancers [36]
Summary
The Hedgehog (Hh) signaling pathway plays a crucial role in growth and patterning during embryonic development. Recent studies suggest a role of this pathway in stem cell self-renewal and in the mobilization of endogenous stem cells for tissue repair and regeneration after injury and disease [1, 2]. After auto-processing and lipid modification, the secreted fully active N-terminal Hedgehog domain (HhN) initiates signaling by binding to its receptor Patched (Ptc), which induces the internalization and the degradation of Ptc, and relieves the inhibition of the signal transducer Smoothened (Smo). Smo is relocalized at the plasma membrane and activated. This triggers a cascade of downstream events. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Authors' Affiliations: 1Universite Nice Sophia Antipolis, CNRS-UMR 7275, Institut de Pharmacologie Moleculaire et Cellulaire, Sophia Antipolis, Valbonne; 2Universite Nice Sophia Antipolis, CNRS-UMR 7277, INSERM U1091, IBV, Parc Valrose, Bat Recherche Sciences Naturelles, Cedex 2; and 3Galapagos SASU, Romainville, France
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