TY - JOUR
T1 - Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells
AU - Rangarajan, Parthasarathy
AU - Subramaniam, Dharmalingam
AU - Paul, Santanu
AU - Kwatra, Deep
AU - Palaniyandi, Kanagaraj
AU - Islam, Shamima
AU - Harihar, Sitaram
AU - Ramalingam, Satish
AU - Gutheil, William
AU - Putty, Sandeep
AU - Pradhan, Rohan
AU - Padhye, Subhash
AU - Welch, Danny R.
AU - Anant, Shrikant
AU - Dhar, Animesh
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - Crocetin
KW - DCLK-1
KW - Gli transcription factor
KW - Nude mice
KW - Pancosphere
UR - http://www.scopus.com/inward/record.url?scp=84944457140&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84944457140&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.4871
DO - 10.18632/oncotarget.4871
M3 - Article
C2 - 26317547
AN - SCOPUS:84944457140
SN - 1949-2553
VL - 6
SP - 27661
EP - 27673
JO - Oncotarget
JF - Oncotarget
IS - 29
ER -
