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Molecular and Cellular Biochemistry

, Volume 373, Issue 1–2, pp 217–227 | Cite as

Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog–GLI pathway

  • Shih-Hui Li
  • Junsheng Fu
  • Dara Nall Watkins
  • Rakesh K. Srivastava
  • Sharmila ShankarEmail author
Article

Abstract

Sulforaphane (SFN), a component of dietary cruciferous vegetables has been characterized for its anti-proliferative properties. We have recently demonstrated that pancreatic CSCs display activation of sonic hedgehog pathway which are fundamental drivers of stem cell renewal, and SFN inhibits the self-renewal of pancreatic CSCs in vitro. Consistent with these observations, we sought to determine the chemopreventive potential of SFN in an in vivo setting. We show here for the first time that sulforaphane treatment resulted in a significant reduction in the tumor growth of orthotopically implanted primary pancreatic CSCs isolated from human pancreatic tumors into the pancreas of NOD/SCID/IL2Rgamma mice, which is mediated through the modulation of Sonic hedgehog–GLI signaling. Hedgehog pathway blockade by SFN at a dose of 20 mg/kg resulted in a 45 % reduction in growth of pancreatic cancer tumors and reduced expression of Shh pathway components, Smo, Gli 1, and Gli 2 in mouse tissues. Further, SFN inhibited the expression of pluripotency maintaining transcription factors Nanog and Oct-4 and angiogenic markers VEGF and PDGFRα which are downstream targets of Gli transcription. Furthermore, SFN treatment resulted in a significant reduction in EMT markers Zeb-1, which correlated with increase in E-Cadherin expression suggesting the blockade of signaling involved in early metastasis. Interestingly, SFN downregulated the expression of Bcl-2 and XIAP to induce apoptosis. These data demonstrate that, at a tolerable dose, inhibition of Shh pathway by SFN results in marked reduction in EMT, metastatic, angiogenic markers with significant inhibition in tumor growth in mice. Since aberrant Shh signaling occurs in pancreatic tumorigenesis, therapeutics that target Shh pathway may improve the outcomes of patients with pancreatic cancer by targeting CSCs, thus suggesting the use of sulforaphane to further improve preventive and therapeutic approaches in patients with this devastating disease.

Keywords

Cancer stem cells Pancreatic cancer Pluripotency maintaining factors Sonic hedgehog pathway Sulforaphane Epithelial–mesenchymal transition 

Notes

Acknowledgments

We thank our lab members for critical reading of the manuscript.

Conflict of interest

The authors indicate no potential conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Shih-Hui Li
    • 1
  • Junsheng Fu
    • 1
  • Dara Nall Watkins
    • 1
  • Rakesh K. Srivastava
    • 2
  • Sharmila Shankar
    • 1
    Email author
  1. 1.Department of Pathology and Laboratory MedicineThe University of Kansas Cancer Center, The University of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Pharmacology, Toxicology and Therapeutics, and MedicineThe University of Kansas Cancer Center, The University of Kansas Medical CenterKansas CityUSA

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