Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells

Parthasarathy Rangarajan, Dharmalingam Subramaniam, Santanu Paul, Deep Kwatra, Kanagaraj Palaniyandi, Shamima Islam, Sitaram Harihar, Satish Ramalingam, William Gutheil, Sandeep Putty, Rohan Pradhan, Subhash Padhye, Danny R. Welch, Shrikant Anant, Animesh Dhar

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)27661-27673
Number of pages13
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Crocetin
  • DCLK-1
  • Gli transcription factor
  • Nude mice
  • Pancosphere

Fingerprint

Dive into the research topics of 'Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells'. Together they form a unique fingerprint.

Cite this