Inhibition of Pancreatic Cancer Stem Cell Characteristics by α‐Mangostin | Rakesh Srivastav

Rakesh K Srivastava The current investigation was intended to elucidate the molecular mechanism of α‐Mangostin in the regulation of pancreatic cancer stem cell (CSC) characteristics. Here, we demonstrate that α‐Mangostin inhibited cell proliferation in pancreatic CSCs and cancer cell lines while it showed no effect on human pancreatic normal ductal epithelial cells. Also, α‐Mangostin inhibited colony formation and induced apoptosis in these cells. Further, α‐Mangostin inhibited the self‐renewal capacity of CSCs isolated from human primary tumours and KrasG12D mice. Furthermore, α‐Mangostin inhibited the invasive and metastatic ability of pancreatic CSCs by suppressing the epithelial‐to‐mesenchymal transition (EMT) via up‐regulation of E‐cadherin and down‐regulation of mesenchymal phenotype by inhibiting N‐cadherin, Snail and Slug expression. Interestingly, the pluripotency maintaining factors and CSC markers were inhibited by α‐Mangostin thus suggesting that α‐Mangostin can target CSCs to inhibit pancreatic cancer effectively. Gli signalling plays a crucial role in the self‐renewal and pluripotency of CSCs. α‐Mangostin inhibited the Gli transcription and the expression of Gli target genes (Nanog, Oct4, c‐Myc, Sox‐2 and KLF4) in CSCs. Using ChIP assay, we demonstrated that Nanog could directly bind to promoters of Cdk2, Cdk6, FGF4, c‐Myc and α‐Mangostin inhibited Nanog binding to these promoters. Conversely, the inhibitory effects of the α‐Mangostin on CSC proliferation and Gli or Nanog transcription and their targets were abrogated by either enforced activation of sonic hedgehog (Shh) or by the overexpression of Nanog. Taken together, our studies suggest that α‐Mangostin may act as Gli inhibitor and establishes the pre‐clinical significance of α‐Mangostin for the prevention and treatment of pancreatic cancer.

Keywords: cancer stem cells, chromatin immunoprecipitation, Nanog, pancreatic cancer, Sonic hedgehog, α‐Mangostin.

1. INTRODUCTION

Pancreatic cancer is a devastating disease and is the fourth most common cause of cancer‐related mortality in the United States.1 Pancreatic cancer exhibits the poorest prognosis from all other cancers, and the overall 5‐year survival rate continues to be less than 6%.2, 3 Pancreatic cancer is characterized by slow growth, late detection and resistance to chemotherapy and radiation and is associated with high mortality rates even after surgery.3 Unfortunately, by the time the disease is diagnosed most of the pancreatic cancer patients present with unresectable advanced malignancy due to early metastasis. Accumulating evidence supports the role of cancer stem cells (CSCs) in cancer initiation, progression, metastasis and chemotherapy failure.4 Despite increased advancement in our understanding of the disease progression, diagnosis and therapeutics, available treatment options are limited. Chemo‐ and radio‐therapies have been largely ineffective and associated with enhanced drug toxicity, drug resistance and frequent redevelopment of the metastatic disease. Further, poor bioavailability of the drug and undesirable side effects are other significant limitations in the effective management of pancreatic cancer. Thus, it is highly desirable to develop an increased understanding of the pathogenesis of the disease, for effective disease management and the development of effective strategies by non‐toxic natural agents for the prevention and treatment of pancreatic cancer.

Hedgehog (Hh) signalling pathway is crucially involved in vertebrate development.5 It is inactive in mature cells of normal adult and found to be aberrantly hyper‐activated in pancreatic cancer and various other malignancies. Evidence suggests that Hh signalling can regulate tissue homeostasis by controlling the production of stem or progenitor cells.6 Deregulation of the Hh signalling pathway is associated with various malignancies. In several of our recent reports, we have demonstrated that for the prevention of pancreatic cancer, a variety of natural products and small molecules displayed antiproliferative properties through targeting the sonic hedgehog (Shh) signalling pathway.7, 8, 9, 10, 11, 12 Upon binding of the Shh ligand to transmembrane Patched (Ptch) receptor results in the withdrawal of inhibitory effects of Patched on smoothened.5 Thus, the pathway is activated via smoothened through Hh protein stimulation or by the loss of patched activity through Ptch mutations. Activation of the Hh pathway via smoothened induces Gli transcriptional activity.

Several reports have demonstrated that Hh pathway activation induces stem cell markers and is involved in the enhancement of epithelial‐to‐mesenchymal transition (EMT) thus regulating metastasis in various malignancies including pancreatic ductal adenocarcinoma.5, 13 The involvement of Shh increases dramatically from PanIN lesions to PDAC to metastatic tumours.14 Therefore, targeting the Shh pathway is regarded as a beneficial strategy for the prevention and treatment of pancreatic cancer.

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