Editors' ChoiceCancer

Extrinsic Resistance to Hedgehog Inhibition

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Science Signaling  07 May 2013:
Vol. 6, Issue 274, pp. ec104
DOI: 10.1126/scisignal.2004306

The Hedgehog (Hh) pathway is critical for development, but it is also implicated in the epithelial-to-mesenchymal transition (EMT) in tumorigenesis and metastasis, processes that are regulated by both cancer cell intrinsic properties and extrinsic signals provided by the surrounding tissue. Osteopontin (OPN) is an inflammatory cytokine secreted by the stroma. Das et al. found that breast cancer cell lines treated with exogenous OPN showed increased activity of the Hh-regulated transcription factor GLI1 and expression of its target PTCH (Patched), increased the expression of genes associated with the mesenchymal phenotype, and decreased the expression of those associated with the epithelial phenotype. Conversely, silencing endogenous OPN in invasive breast cancer cell lines suppressed the activity of GLI1 and induced the expression of epithelial phenotype–related genes. GANT61, a GLI1 inhibitor, antagonized the OPN-induced transcriptional repression of epithelial marker keratin 18 and inhibited the transcription of numerous mesenchymal markers. Breast cancer cell lines treated with OPN had reduced cytotoxicity to various chemotherapeutics and increased abundance of multidrug resistance proteins MDR1 and BCRP (breast cancer resistance protein), effects that were also inhibited by GANT61 or GLI1 silencing. The Smoothened inhibitor cyclopamine did not block the effects of OPN, indicating that OPN’s effects on GLI1 were independent of Smoothened. This may occur through the inactivation of GSK3β (glycogen synthase kinase 3β), because OPN induced the inhibitory phosphorylation of endogenous GSK3β in breast cancer cells, which was associated with the translocation of GLI1 to the nucleus. Cells transfected with constitutively active GSK3β exhibited increased drug concentrations, which were reduced by addition of OPN. Because OPN is also transcriptionally activated by GLI1 in response to Hh, and OPN promotes GLI1 activity, the findings suggest a destructive feed-forward cycle that promotes EMT and multidrug resistance in cancer.

S. Das, R. S. Samant, L. A. Shevde, Nonclassical activation of Hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to Smoothened-targeting Hedgehog inhibition. J. Biol. Chem. 288, 11824–11833 (2013). [Abstract] [Full Text]

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