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Molecular Pharmacology

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Research ArticleArticle

Arsenic Attenuates GLI Signaling, Increasing or Decreasing its Transcriptional Program in a Context-Dependent Manner

Bin Li, Camilla Giambelli, Bo Tang, Emily Winterbottom, Jun Long, Ke Jin, Zhiqiang Wang, Dennis Liang Fei, Dao M. Nguyen, Mohammad Athar, Baolin Wang, Pochi R. Subbarayan, Lily Wang, Priyamvada Rai, Bach Ardalan, Anthony J. Capobianco and David J. Robbins
Molecular Pharmacology February 2016, 89 (2) 226-232; DOI: https://doi.org/10.1124/mol.115.100867
Bin Li
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Camilla Giambelli
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Bo Tang
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Emily Winterbottom
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Jun Long
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Ke Jin
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Zhiqiang Wang
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Dennis Liang Fei
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Dao M. Nguyen
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Mohammad Athar
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Baolin Wang
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Pochi R. Subbarayan
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Lily Wang
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Priyamvada Rai
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Bach Ardalan
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Anthony J. Capobianco
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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David J. Robbins
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida (B.L., C.G., E.W., J.L., K.J., Z.W., D.L.F., D.M.N., A.J.C., D.J.R.); General Surgery Center of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China (B.T.); Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, Florida (J.L.); Program in Experimental and Molecular Medicine, Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (D.L.F.); Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida (D.M.N., P.R.S., P.R., B.A., A.J.C., D.J.R.); Department of Dermatology, University of Alabama, Birmingham, Alabama (M.A.); Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York (B.W.); Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida (L. W.); Departments of Medicine (P.R.S., P.R., B.A.) and Biochemistry and Molecular Biology (A.J.C., D.J.R.), Miller School of Medicine, University of Miami, Miami, Florida; and Division of Geriatric Medicine and Palliative Care, Miller School of Medicine, University of Miami, Miami, Florida (P.R.)
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Abstract

The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic’s biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

Footnotes

    • Received July 14, 2015.
    • Accepted November 13, 2015.
  • B.L., C.G., and B.T. contributed equally to this work.

  • This research was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P01ES01817502], the National Institutes of Health National Institute of General Medical Sciences [Grant GM64011], and the National Institutes of Health National Cancer Institute [Grant 1R21CA117116-01]

  • dx.doi.org/10.1124/mol.115.100867.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (2)
Molecular Pharmacology
Vol. 89, Issue 2
1 Feb 2016
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Arsenic Attenuates GLI Signaling, Increasing or Decreasing its Transcriptional Program in a Context-Dependent Manner
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Research ArticleArticle

Arsenic Trioxide Plays Dual Roles in GLI-Dependent Signaling

Bin Li, Camilla Giambelli, Bo Tang, Emily Winterbottom, Jun Long, Ke Jin, Zhiqiang Wang, Dennis Liang Fei, Dao M. Nguyen, Mohammad Athar, Baolin Wang, Pochi R. Subbarayan, Lily Wang, Priyamvada Rai, Bach Ardalan, Anthony J. Capobianco and David J. Robbins
Molecular Pharmacology February 1, 2016, 89 (2) 226-232; DOI: https://doi.org/10.1124/mol.115.100867

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Research ArticleArticle

Arsenic Trioxide Plays Dual Roles in GLI-Dependent Signaling

Bin Li, Camilla Giambelli, Bo Tang, Emily Winterbottom, Jun Long, Ke Jin, Zhiqiang Wang, Dennis Liang Fei, Dao M. Nguyen, Mohammad Athar, Baolin Wang, Pochi R. Subbarayan, Lily Wang, Priyamvada Rai, Bach Ardalan, Anthony J. Capobianco and David J. Robbins
Molecular Pharmacology February 1, 2016, 89 (2) 226-232; DOI: https://doi.org/10.1124/mol.115.100867
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