Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector.
Aberrant Hedgehog (Hh) pathway activation has been implicated in cancers of diverse tissues and organs, and the tumor growth-inhibiting effects of pathway antagonists in animal models have stimulated efforts to develop pathway antagonists for human therapeutic purposes. These efforts have focused largely on cyclopamine derivatives or other compounds that mimic cyclopamine action in binding to and antagonizing Smoothened, a membrane transductory component. We report here that arsenicals, in contrast, antagonize the Hh pathway by targeting Gli transcriptional effectors; in the short term, arsenic blocks Hh-induced ciliary accumulation of Gli2, the primary activator of Hh-dependent transcription, and with prolonged incubation arsenic reduces steady-state levels of Gli2. Arsenicals active in Hh pathway antagonism include arsenic trioxide (ATO), a curative agent in clinical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway-driven medulloblastoma allografts derived from Ptch+/-p53-/- mice within a range of serum levels comparable to those achieved in treatment of human APL. Arsenic thus could be tested rapidly as a therapeutic agent in malignant diseases associated with Hh pathway activation and could be particularly useful in such diseases that are inherently resistant or have acquired resistance to cyclopamine mimics.
Kim
Jynho
J
Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Lee
John J
JJ
Kim
James
J
Gardner
Dale
D
Beachy
Philip A
PA
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D010087:Oxides / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000494:pharmacology; D014162:Transfection; D014184:Transplantation, Homologous; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D000075746:Zinc Finger Protein Gli2
D001152:Arsenicals; D018053:Arsenites; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008164:Luminescent Proteins; D010087:Oxides; D011993:Recombinant Fusion Proteins; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; D000075746:Zinc Finger Protein Gli2; C029341:oxophenylarsine; C017947:sodium arsenite; D008156:Luciferases; D000077237:Arsenic Trioxide