title: Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity.
abstract: A number of Smoothened (SMO) pathway antagonists are currently undergoing clinical trials as anticancer agents. These drugs are proposed to attenuate tumor growth solely through inhibition of Hedgehog (HH), which is produced in tumor cells but acts on tumor stromal cells. The pivotal argument underlying this model is that the growth-inhibitory properties of SMO antagonists on HH-producing cancer cells are due to their off-target effects. Here, we show that the tumorigenic properties of such lung cancer cells depend on their intrinsic level of HH activity. Notably, reducing HH signaling in these tumor cells decreases HH target gene expression. Taken together, these results question the dogma that autocrine HH signaling plays no role in HH-dependent cancers, and does so without using SMO antagonists.
authors.affiliation: Department of Surgery; Sylvester Cancer Center; Department of Biochemistry and Molecular Biology, Braman Family Breast Cancer Institute, Miller School of Medicine, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors.forename: Samer
authors.initials: S
authors.lastname: Singh
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Dennis
authors.initials: D
authors.lastname: Liang Fei
authors.forename: Kendall E
authors.initials: KE
authors.lastname: Black
authors.forename: John A
authors.initials: JA
authors.lastname: Goetz
authors.forename: Robert
authors.initials: R
authors.lastname: Tokhunts
authors.forename: Camilla
authors.initials: C
authors.lastname: Giambelli
authors.forename: Jezabel
authors.initials: J
authors.lastname: Rodriguez-Blanco
authors.forename: Jun
authors.initials: J
authors.lastname: Long
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.forename: Karoline J
authors.initials: KJ
authors.lastname: Briegel
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Bejarano
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1