title: Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells.
abstract: Pancreatic cancer is the fourth leading cause of cancer deaths in the US and no significant treatment is currently available. Here, we describe the effect of crocetinic acid, which we purified from commercial saffron compound crocetin using high performance liquid chromatography. Crocetinic acid inhibits proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. In addition, it induced apoptosis. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, crocetinic acid decreased the number and size of the pancospheres in a dose-dependent manner, and suppressed the expression of the marker protein DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1) suggesting that crocetinic acid targets cancer stem cells (CSC). To understand the mechanism of CSC inhibition, the signaling pathways affected by purified crocetinic acid were dissected. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Crocetinic acid inhibited the expression of both Shh and smoothened. Finally, these data were confirmed in vivo where the compound at a dose of 0.5 mg/Kg bw suppressed growth of tumor xenografts. Collectively, these data suggest that purified crocetinic acid inhibits pancreatic CSC, thereby inhibiting pancreatic tumorigenesis.
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Parthasarathy
authors: P
authors: Rangarajan
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Dharmalingam
authors: D
authors: Subramaniam
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Santanu
authors: S
authors: Paul
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Deep
authors: D
authors: Kwatra
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Kanagaraj
authors: K
authors: Palaniyandi
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Shamima
authors: S
authors: Islam
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Sitaram
authors: S
authors: Harihar
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Satish
authors: S
authors: Ramalingam
authors: Department of Pharmaceutical Sciences, University of Missouri at Kansas City, Kansas City, MO, USA.
authors: William
authors: W
authors: Gutheil
authors: Department of Pharmaceutical Sciences, University of Missouri at Kansas City, Kansas City, MO, USA.
authors: Sandeep
authors: S
authors: Putty
authors: Interdisciplinary Science and Technology Research Academy, Abeda Inamdar College, University of Pune, Pune, India.
authors: Rohan
authors: R
authors: Pradhan
authors: Interdisciplinary Science and Technology Research Academy, Abeda Inamdar College, University of Pune, Pune, India.
authors: Subhash
authors: S
authors: Padhye
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Danny R
authors: DR
authors: Welch
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Shrikant
authors: S
authors: Anant
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Animesh
authors: A
authors: Dhar
mesh_terms: D000818:Animals; D017209:Apoptosis; D002338:Carotenoids / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D027622:Crocus / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D000089742:Doublecortin-Like Kinases; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D010936:Plant Extracts / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D018874:Spheroids, Cellular / Q000378:metabolism; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; D014801:Vitamin A / Q000031:analogs & derivatives
chemical_list: D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010936:Plant Extracts; D043562:Receptors, G-Protein-Coupled; C099021:SHC2 protein, human; C509239:SHH protein, human; C491023:SMO protein, human; D055765:Shc Signaling Adaptor Proteins; D000072086:Smoothened Receptor; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases
keywords: DCLK-1; Gli transcription factor; crocetin; nude mice; pancosphere