Abstract
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.
Highlights
Pancreatic cancer (PC) has one of the poorest prognoses among all cancers and overall 5-year survival rate of 3% [1,2,3]
We have previously shown that oral administration of sulforaphane inhibited the growth of PC-3 cells orthotopically implanted in the prostate of nude mice by inducing apoptosis and inhibiting tumor cell proliferation, metastasis and angiogenesis [19]
To evaluate the possibility that the Hh signaling is active in human pancreatic cancer stem cells (CSC) we compared the mRNA expression of various components of the sonic hedgehog (Shh) pathway in human pancreatic CSC (PanCSC) to human pancreatic normal ductal epithelial cells (HPNE) and human normal pancreatic stem cells (HNPSC), in an in vitro cell culture model and as quantified by qRT-PCR
Summary
Pancreatic cancer (PC) has one of the poorest prognoses among all cancers and overall 5-year survival rate of 3% [1,2,3]. There is an urgent need to discover novel and effective chemopreventive approaches for pancreatic cancer. The CSC hypothesis suggests that only the stem cell compartment in tumors is capable of unlimited selfrenewal and that elimination of these cells will halt neoplastic expansion, as better-differentiated cells have limited mitogenic capacity and will not contribute to long-term tumor growth. It is imperative to design new strategies based upon a better understanding of the signaling pathways that control aspects of self-renewal and survival in CSCs in order to identify novel therapeutic targets in these cells. Development of therapeutic strategies that target pancreatic CSCs can be effective in eradicating tumors and in reducing the risk of relapse and metastasis
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