S Safe


Affiliation: Texas A and M University
Country: USA


  1. Hedrick E, Lee S, Doddapaneni R, Singh M, Safe S. Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy. Endocr Relat Cancer. 2015;22:831-40 pubmed publisher
    ..They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor. ..
  2. Lacey A, Hedrick E, Cheng Y, Mohankumar K, Warren M, Safe S. Interleukin-24 (IL-24) Is Suppressed By PAX3-FOXO1 and Is A Novel Therapy For Rhabdomyosarcoma. Mol Cancer Ther. 2018;: pubmed publisher
    ..Since adenoviral IL-24 has already successfully undergone Phase I in clinical trials, this represents an alternative approach (alone and/or combination) for treating ARMS patients who currently undergo cytotoxic drug therapies. ..
  3. Hedrick E, Mohankumar K, Safe S. TGF?-induced Lung Cancer Cell Migration Is NR4A1-dependent. Mol Cancer Res. 2018;: pubmed publisher
    ..i>Mol Cancer Res; 1-12. ©2018 AACR. ..
  4. Karki K, Harishchandra S, Safe S. Bortezomib Targets Sp Transcription Factors in Cancer Cells. Mol Pharmacol. 2018;94:1187-1196 pubmed publisher
    ..These results demonstrate that an important underlying mechanism of action of bortezomib was due to the activation of caspase-8-dependent downregulation of Sp1, Sp3, Sp4, and pro-oncogenic Sp-regulated genes. ..
  5. Sreevalsan S, Safe S. The cannabinoid WIN 55,212-2 decreases specificity protein transcription factors and the oncogenic cap protein eIF4E in colon cancer cells. Mol Cancer Ther. 2013;12:2483-93 pubmed publisher
    ..quot; The results show that the anticancer activity of WIN is due, in part, to PP2A-dependent disruption of miR-27a:ZBTB10 and ZBTB10-mediated repression of Sp transcription factors and Sp-regulated genes, including eIF4E. ..
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    Safe S. Endocrine disruptors and human health: is there a problem. Toxicology. 2004;205:3-10 pubmed
    ..In contrast, testicular cancer is increasing in most countries, and causal environmental/lifestyle factors for this disease are unknown. ..
  7. Safe S, Abbruzzese J, Abdelrahim M, Hedrick E. Specificity Protein Transcription Factors and Cancer: Opportunities for Drug Development. Cancer Prev Res (Phila). 2018;11:371-382 pubmed publisher
    ..The effects of these compounds on downregulation of Sp TFs in normal cells and the contribution of this response to their chemopreventive activity have not yet been determined. Cancer Prev Res; 11(7); 371-82. ©2018 AACR. ..
  8. Safe S. 3-methylcholanthrene induces differential recruitment of aryl hydrocarbon receptor to human promoters. Toxicol Sci. 2010;117:1-3 pubmed publisher
    ..TCDD)-dependent AHR bound regions. The results illustrate the complexity of AHR signaling and also demonstrate that compared with TCDD as a reference ligand, 3MC is a selective AHR modulator. ..
  9. Safe S. MicroRNA-Specificity Protein (Sp) Transcription Factor Interactions and Significance in Carcinogenesis. Curr Pharmacol Rep. 2015;1:73-78 pubmed

More Information


  1. Hedrick E, Crose L, Linardic C, Safe S. Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors. Mol Cancer Ther. 2015;14:2143-53 pubmed publisher
  2. Safe S, Jin U, Morpurgo B, Abudayyeh A, Singh M, Tjalkens R. Nuclear receptor 4A (NR4A) family - orphans no more. J Steroid Biochem Mol Biol. 2016;157:48-60 pubmed publisher
  3. Jin U, Karki K, Kim S, Safe S. Inhibition of pancreatic cancer Panc1 cell migration by omeprazole is dependent on aryl hydrocarbon receptor activation of JNK. Biochem Biophys Res Commun. 2018;501:751-757 pubmed publisher
  4. Kasiappan R, Jutooru I, Karki K, Hedrick E, Safe S. Benzyl Isothiocyanate (BITC) Induces Reactive Oxygen Species-dependent Repression of STAT3 Protein by Down-regulation of Specificity Proteins in Pancreatic Cancer. J Biol Chem. 2016;291:27122-27133 pubmed publisher
  5. Moore R, Fritz W, Schneider A, Lin T, Branam A, Safe S, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice. Toxicol Appl Pharmacol. 2016;305:242-249 pubmed publisher
    ..Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures. ..
  6. Kolluri S, Jin U, Safe S. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol. 2017;91:2497-2513 pubmed publisher
    ..This review describes the anti-cancer activities of AhR ligands and demonstrates that it is time to separate the AhR from TCDD and exploit the potential of the AhR as a novel target for cancer chemotherapy. ..
  7. Jutooru I, Guthrie A, Chadalapaka G, Pathi S, Kim K, Burghardt R, et al. Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents. Mol Cell Biol. 2014;34:2382-95 pubmed publisher
  8. Safe S, Lee S, Jin U. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol Sci. 2013;135:1-16 pubmed publisher
  9. request reprint
    Safe S, Abdelrahim M. Sp transcription factor family and its role in cancer. Eur J Cancer. 2005;41:2438-48 pubmed
    ..Sp/KLF proteins are also potential targets for cancer chemotherapy. ..
  10. Jin U, Lee S, Pfent C, Safe S. The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer. 2014;14:498 pubmed publisher
    ..AHR-active pharmaceuticals such as omeprazole that decrease breast cancer cell invasion and metastasis may have important clinical applications for late stage breast cancer chemotherapy. ..
  11. Safe S, Kim K, Kim K. Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. J Mol Endocrinol. 2008;41:263-75 pubmed publisher
  12. Li X, Pathi S, Safe S. Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors. BMC Cancer. 2015;15:974 pubmed publisher
  13. Jin U, Cheng Y, Zhou B, Safe S. Bardoxolone Methyl and a Related Triterpenoid Downregulate cMyc Expression in Leukemia Cells. Mol Pharmacol. 2017;91:438-450 pubmed publisher
  14. Safe S, Kasiappan R. Natural Products as Mechanism-based Anticancer Agents: Sp Transcription Factors as Targets. Phytother Res. 2016;30:1723-1732 pubmed publisher
    ..Copyright © 2016 John Wiley & Sons, Ltd. ..
  15. Hedrick E, Li X, Safe S. Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors. Mol Cancer Ther. 2017;16:205-216 pubmed publisher
    ..Mol Cancer Ther; 16(1); 205-16. ©2016 AACR. ..
  16. Cheng Y, Jin U, Davidson L, Chapkin R, Jayaraman A, Tamamis P, et al. Editor's Highlight: Microbial-Derived 1,4-Dihydroxy-2-naphthoic Acid and Related Compounds as Aryl Hydrocarbon Receptor Agonists/Antagonists: Structure-Activity Relationships and Receptor Modeling. Toxicol Sci. 2017;155:458-473 pubmed publisher
    ..We also used computational analysis to show that 1,4-DHNA and TCDD share similar interactions within the AhR binding pocket and differ primarily due to the negatively charged group of 1,4-DHNA. ..
  17. Lacey A, Rodrigues Hoffman A, Safe S. PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1. Cancer Res. 2017;77:732-741 pubmed publisher
    ..Taken together, our results provide a preclinical rationale for the use of NR4A1 small-molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A. Cancer Res; 77(3); 732-41. ©2016 AACR. ..
  18. Safe S, Papineni S, Chintharlapalli S. Cancer chemotherapy with indole-3-carbinol, bis(3'-indolyl)methane and synthetic analogs. Cancer Lett. 2008;269:326-38 pubmed publisher
  19. Hedrick E, Lee S, Doddapaneni R, Singh M, Safe S. NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration. Mol Cell Biol. 2016;36:1383-94 pubmed publisher
  20. Nair V, Sreevalsan S, Basha R, Abdelrahim M, Abudayyeh A, Rodrigues Hoffman A, et al. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J Biol Chem. 2014;289:27692-701 pubmed publisher
    ..Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively. ..
  21. Chintharlapalli S, Papineni S, Lei P, Pathi S, Safe S. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer. 2011;11:371 pubmed publisher
    ..These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent. ..
  22. Gandhy S, Kim K, Larsen L, Rosengren R, Safe S. Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC Cancer. 2012;12:564 pubmed publisher
  23. Jin U, Cheng Y, Park H, Davidson L, Callaway E, Chapkin R, et al. Short Chain Fatty Acids Enhance Aryl Hydrocarbon (Ah) Responsiveness in Mouse Colonocytes and Caco-2 Human Colon Cancer Cells. Sci Rep. 2017;7:10163 pubmed publisher
    ..These results demonstrate SCFA-AhR ligand interactions in YAMC and Caco-2 cells where SCFAs synergistically enhance basal and ligand-induced expression of AhR-responsive genes. ..
  24. Safe S. Carbidopa: a selective Ah receptor modulator (SAhRM). Biochem J. 2017;474:3763-3765 pubmed publisher
    ..These results are consistent with activities of other AhR-active compounds that inhibit carcinogenesis. Like carbidopa, these chemicals are selective AhR modulators with potential clinical applications that are AhR-dependent...
  25. Hedrick E, Safe S. Transforming Growth Factor β/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38α (Mitogen-Activated Protein Kinase 14) Dependent. Mol Cell Biol. 2017;37: pubmed publisher
  26. Karki K, Hedrick E, Kasiappan R, Jin U, Safe S. Piperlongumine Induces Reactive Oxygen Species (ROS)-Dependent Downregulation of Specificity Protein Transcription Factors. Cancer Prev Res (Phila). 2017;10:467-477 pubmed publisher
    ..i>Cancer Prev Res; 10(8); 467-77. ©2017 AACR. ..
  27. Cheng Y, Jin U, Allred C, Jayaraman A, Chapkin R, Safe S. Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes. Drug Metab Dispos. 2015;43:1536-43 pubmed publisher
    ..These results suggest that the tryptophan metabolites identified in microbiota are selective AhR modulators. ..
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    Abdelrahim M, Safe S. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol. 2005;68:317-29 pubmed
    ..These results suggest that the antiangiogenic activity of COX-2 inhibitors in colon cancer cells is linked to activation of proteasome-dependent degradation of Sp1 and Sp4 proteins. ..
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    Safe S, Wormke M, Samudio I. Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells. J Mammary Gland Biol Neoplasia. 2000;5:295-306 pubmed