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 is a Hedgehog signaling target gene that is over-expressed in many cancer cells. Here, we demonstrate a link between Patched and resistance to chemotherapy, and provide new insight into Patched function. Patched 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 demonstrated that the expression of human Patched 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 Patched function, as shown using Patched mutations from Gorlin's syndrome patients in which the Patched-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.