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 citas
Etiquetas de revisión
Solo mecanismosDatos neutrales que nuestra revisión registró sobre cómo se hizo este estudio. Describen el método, nunca si nos gusta el resultado.
Cómo se estudió
- Diseño
- Estudio in vitro o de mecanismos (clasificado por nuestro filtro de IA)
- Estudiado en
- Células o muestras de laboratorio
- Resultado principal
- Solo mecanismos
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- U.S. Department of Veterans Affairs
- Gobierno
- BLRD VA
- Subvenciones
- U.S. Department of Veterans Affairs (I01 BX001583)
Según 2 financiadores declarados y la declaración de financiación del texto completo.
Publicación
- Publicado
- 2012-09-28 · PLoS One · vol. 7 · número 9 · pág. e46083
- Editorial
- Public Library of Science
- Citado
- 119 citas · más que el 98% de estudios similares · 6.3× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 44 trabajos
- Acceso
- Acceso abierto (revista) · PUBLIC-DOMAIN
- Áreas de investigación
- Hedgehog Signaling Pathway Studies · Epigenetics and DNA Methylation · Cancer Cells and Metastasis
- Palabras clave
- 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 autores
- Mariana Rodova🇺🇸The University of Kansas Cancer Center; University of Kansas Medical Center
- Junsheng Fu🇺🇸The University of Kansas Cancer Center; University of Kansas Medical Center
- Dara Nall Watkins🇺🇸The University of Kansas Cancer Center; University of Kansas Medical Center
- Rakesh K. Srivastava🇺🇸The University of Kansas Cancer Center; University of Kansas Medical Center
- Sharmila Shankar🇺🇸 · autor de correspondenciaThe University of Kansas Cancer Center; University of Kansas Medical Center
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
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