The current obstacles for discovering new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the identification of new uses for approved or investigational drugs for new therapeutic purposes. Niclosamide (Nic) is a Food and Drug Administration (FDA)-approved anti-helminthic drug, reported to have anti-cancer effects, and is being assessed in various clinical trials. In the current study, we assessed the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. Our results revealed mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. This study provided a novel mechanistic insight for anti-cancer efficacy of Nic by increasing p-Gsk3β that modulates molecular signaling(s), including inhibition of hedgehog (Hh) signaling-mediated cellular proliferation and increased apoptosis through mTORC1-dependent autophagy may prove helpful for the development of novel PC therapies.

Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.

• Gsk3β
• Hh signaling
• apoptosis
• autophagy
• niclosamide
• pancreatic cancer

• KRAS mutation
• NF-κB pathway
• crosstalk mechanism
• hedgehog pathway
• pancreatic ductal adenocarcinoma

• cancer genomics
• differential targeting
• gene regulatory networks
• gene targeting
• network medicine

• R01 CA199064 NCI NIH HHS
• U24 CA231846 NCI NIH HHS
• K25 HL140186 NHLBI NIH HHS
• K25 HL133599 NHLBI NIH HHS
• R35 CA220523 NCI NIH HHS

• ChIP-Seq
• PDAC
• cancer stem cells
• super-enhancers
• therapeutics

• Cancer stem cells
• DCLK1
• chemoprevention
• natural compounds
• pancreatic cancer
• signaling.

Since the discovery of the Hedgehog (Hh) pathway in drosophila melanogaster, our knowledge of the role of Hh in embryonic development, inflammation, and cancerogenesis in humans has dramatically increased over the last decades. This is the case especially concerning the pancreas, however, real therapeutic breakthroughs are missing until now. In general, Hh signaling is essential for pancreatic organogenesis, development, and tissue maturation. In the case of acute pancreatitis, Hh has a protective role, whereas in chronic pancreatitis, Hh interacts with pancreatic stellate cells, leading to destructive parenchym fibrosis and atrophy, as well as to irregular tissue remodeling with potency of initiating cancerogenesis. In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment. The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials (phases 1 and 2). Furthermore, a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach. In this review, we give a structured survey of the role of the Hh pathway in pancreatic development, pancreatitis, pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.

• Pancreatic cancer
• Hedgehog
• Pancreatitis
• Pancreas
• Development

Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells.

SHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2.

SHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95 % CI: 1.109–2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival.

Increased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.

• Autocrine
• Gastric cancer
• Prognosis
• Proliferation
• Sonic hedgehog

MiR-200a has been reported to be able to suppress the epithelial-mesenchymal transition process in pancreatic cancer stem cells, suggesting that miR-200a could suppress the metastasis of pancreatic ductal adenocarcinoma (PDAC). However, its role in proliferation and metastasis of PDAC and the underlying mechanism by which miR-200a works in PDAC have not been elucidated. In our study, we for the first time identified that DEK gene is a direct downstream target of miR-200a. It was found that overexpression of miR-200a decreased DEK expression, suppressing the proliferation, migration, and invasion of PDAC cells. Meanwhile, knockdown of miR-200a can increase DEK level, promoting the proliferation, migration, and invasion of PDAC cells. Our study demonstrated that miR-200a suppresses the metastasis in pancreatic PDAC through downregulation of DEK, suggesting that miR-200a may be used as a novel potential marker in prediction of metastasis of PDAC.

• GCMa
• GLI2
• Hedgehog signaling pathway
• cell fusion
• complex
• placenta
• protein stability
• transactivation
• trophoblast

Hedgehog (Hh) signaling pathway consists of ligands such as Hh, receptor (patched), transmembrane protein Smo, nuclear transcription factor Gli, and downstream target genes. This pathway plays an important role in cell differentiation, tissue development and organ formation in the embryonic stage. In recent years, the Hh signaling pathway has been reported to play an important role in the development of pancreatic cancer. It can induce differentiation, proliferation and invasion of pancreatic cancer cells. Blocking the Hh signaling pathway in pancreatic cancer cells will provide a new and effective method for the treatment of pancreatic cancer. In this review, we will summarize the composition of the Hh signaling pathway and its relationship with the development of pancreatic cancer.

• Hedgehog
• Signaling pathway
• Pancreatic cancer