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.