Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal
Rodova M, Fu J, Watkins DN, Srivastava RK, Shankar S
PloS one · 90 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- Cells or lab samples
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Government
- U.S. Department of Veterans Affairs
- Government
- BLRD VA
- Grants
- U.S. Department of Veterans Affairs (I01 BX001583)
Based on 2 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2012-09-28 · PLoS One · vol. 7 · issue 9 · p. e46083
- Publisher
- Public Library of Science
- Cited
- 119 citations · more than 98% of similar papers · 6.3× the field average
- Impact
- Top 10% most cited in its field
- References
- 44 works
- Access
- Open access (journal) · PUBLIC-DOMAIN
- Research areas
- Hedgehog Signaling Pathway Studies · Epigenetics and DNA Methylation · Cancer Cells and Metastasis
- Keywords
- Cyclopamine, Pancreatic cancer, Cancer stem cell, Cancer research, Sonic hedgehog, Hedgehog signaling pathway, Sulforaphane, Homeobox protein NANOG, PDX1, Biology, Stem cell, GLI1, Hedgehog, Cell biology, Signal transduction, Cancer, Transcription factor, Embryonic stem cell, Induced pluripotent stem cell, Biochemistry
- MeSH
- pancreas, cell line, tumor, humans, pancreatic neoplasms, thiocyanates, isothiocyanates, sulfoxides, transcription factors, anticarcinogenic agents, signal transduction, apoptosis, cell proliferation, gene expression regulation, neoplastic, hedgehog proteins, neoplastic stem cells, zinc finger protein gli1
5 authors
From US
- Mariana RodovaThe University of Kansas Cancer Center; University of Kansas Medical Center
- Junsheng FuThe University of Kansas Cancer Center; University of Kansas Medical Center
- Dara Nall WatkinsThe University of Kansas Cancer Center; University of Kansas Medical Center
- Rakesh K. SrivastavaThe University of Kansas Cancer Center; University of Kansas Medical Center
- Sharmila Shankar · correspondingThe University of Kansas Cancer Center; University of Kansas Medical Center
Abstract
Dysregulation of the sonic hedgehog (Shh) signaling pathway has been associated with cancer stem cells (CSC) and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN), an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC0).
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