Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells
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Parthasarathy Rangarajan2, Dharmalingam Subramaniam2, Santanu Paul1, Deep Kwatra2, Kanagaraj Palaniyandi1, Shamima Islam1, Sitaram Harihar1, Satish Ramalingam2, William Gutheil3, Sandeep Putty3, Rohan Pradhan4, Subhash Padhye4, Danny R. Welch1,2, Shrikant Anant1,2, Animesh Dhar1,2
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
2Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
3Department of Pharmaceutical Sciences, University of Missouri at Kansas City, Kansas City, MO, USA
4Interdisciplinary Science and Technology Research Academy, Abeda Inamdar College, University of Pune, Pune, India
Animesh Dhar, e-mail: [email protected]
Keywords: crocetin, nude mice, pancosphere, DCLK-1, gli transcription factor
Received: April 02, 2015 Accepted: July 31, 2015 Published: August 13, 2015
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.
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