Curcumin inhibits hypoxia-induced epithelial-mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway

Abstract

Abstract. Hypoxic microenvironment, a common feature of pancreatic cancer, is associated with tumor proliferation, metastasis and epithelial-mesenchymal transition (EMT) changes. In recent years, many natural agents, including curcumin, have been proven to possess the ability to inhibit the progression of pancreatic cancer. However, whether curcumin is able to suppress hypoxia-induced pancreatic cancer progression and the underlying mechanisms are still not fully elucidated. The aim of the present study was to evaluate whether curcumin affects hypoxia-induced EMT and the activation of Hh signaling pathway in pancreatic cancer. The human pancreatic cancer cell line Panc-1, was treated with hypoxic condition and curcumin. Cell proliferation was assessed by the MTT assay. Wound healing assay and Transwell invasion assay were used to detect the migratory and invasive activity of cancer cells. The EMT-related factors, E-cadherin, N-cadherin, vimentin were detected by QT-PCR, western blot analysis and immunofluorescence staining. The Hh signaling-related factors, SHH, SMO and GLI1 were detected by western blot analysis. The results of present study showed that curcumin could not only inhibit the hypoxia-induced cell proliferation, migration and invasion in pancreatic cancer, but also mediate the expression of EMT-related factors. In addition, curcumin remarkably inhibited hypoxia-mediated activation of Hh signaling pathway. Taken together, these data indicate that curcumin plays an important role in suppressing hypoxiainduced pancreatic cancer metastasis by inhibiting the Hh signaling pathway. Curcumin might be a potential candidate for chemoprevention of this severe disease. IntroductionPancreatic cancer is one of the most aggressive malignant diseases with a median survival time of less than 6 months and a 5-year survival rate of <5% (1). In 2015, it was estimated that 48,960 subjects will be newly diagnosed with pancreatic cancer and will account for 40,560 cancer-related deaths in the United States (1). Surgical resection remains the only way to cure this severe disease, however, due to the high metastatic rate, the majority of patients are diagnosed at an advanced inoperable stage, and less than 20% of patients are amenable for surgery (2). Even those patients with seemingly resectable pancreatic tumor are not always cured by surgery due to the microscopic systemic spread of cancer cells before the operation intervention (3). Currently, there are very limited therapeutic options for pancreatic cancer, therefore, more constructive and effective interventions for targeting cancer metastasis are urgently needed.Hypoxia (low oxygen tension) is commonly found in solid tumors more than a few millimeters in size and is associated with a poor prognosis (4,5). Tumor hypoxia is strongly associated with enhanced tumor invasiveness, angiogenesis and distant metastasis (4). Hypoxia-inducible factor-1 (HIF-1), which belongs to the basic helix-loop-helix-periodic acidSchiff domain transcription factor family, is a key mediator ...

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

“…Curcumin is a bioactive natural compound, which has been proven to restrain initiation, progression and metastasis of multifarious tumors, including pancreatic cancer (8). More importantly, curcumin is associated with minimal toxicity and it is safe at a high dose, as demonstrated by human clinical trials, in contrast with conventional cytotoxic drugs (35).…”

“…Curcumin exerts its anticancer effects by targeting multiple intracellular signaling pathways, including mitogen-activated protein kinase (MAPK), nuclear factor (NF)-κB, Akt and Wnt/β-catenin, among others (5)(6)(7). In addition, we recently demonstrated that curcumin inhibited hypoxia-induced epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cells via blockade of the hedgehog signaling pathway (8).…”

“…The hallmark of EMT is the loss of E-cadherin expression (an epithelial marker) and the gain of vimentin and N-cadherin expression (mesenchymal markers) (10). We previously demonstrated that several factors could induce EMT in pancreatic cancer cells, including hypoxic (8) and hyperglycemic environment (11), as well as the induction of superoxide dismutase (SOD) (12).…”

Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway

“…38 Especially for high-grade gliomas, the activation or inhibtion of the Hedgehog signaling pathway has a remarkable impact on cell proliferation. 39 There are also numbers of research revealed that Curcumin has specific regulation to Hedgehog signaling pathway and EMT process 7,40,41 in several cancer cells including pancreas, colon, leukemia, prostate carcinoma and glioblastomas. 8,[42][43][44] Islam SS et al and Xu X et al 9,10 point out that the Hedgehog signaling pathway activates EMT process to promote tumorigenicity and stemness.…”

“…[4][5][6] In our previous researches, we illustrated that Curcumin, the ingredient of turmeric, suppressed the activity of Hedgehog signaling pathway by mediating the protein expression including Gli1, SMO and Sufu. 7,8 And Curcumin could also prevent the EMT in different tumor cells. 9,10 With the interruption of EMT, Curcumin might cover the shortage of g-irradiation (induction of EMT).…”