Resveratrol inhibits hyperglycemia-driven ROS-induced invasion and migration of pancreatic cancer cells via suppression of the ERK and p38 MAPK signaling pathways.
Increasing evidence suggests that there is a strong relationship between diabetes mellitus (DM) and pancreatic cancer. Our previous study revealed that hyperglycemia could enhance the invasive and migratory activities of pancreatic cancer cells. Resveratrol, a natural polyphenolic phytoalexin, has many biological and pharmaceutical properties, including antioxidant and anti-tumorigenic capabilities. The aim of the present study was to evaluate whether resveratrol affects hyperglycemia-induced reactive oxygen species (ROS) production as well as the invasion and migration of pancreatic cancer and its underlying mechanisms. Human pancreatic cancer Panc-1 cells were exposed to high glucose condition with or without resveratrol, N-acetylcysteine (NAC, a scavenger of free radicals), PD 98059 (an ERK inhibitor) or SB 203580 (a p38 MAPK inhibitor). The intracellular ROS and hydrogen peroxide (H2O2) were determined using 2,7-dichlorodihydrofluorecein diacetate and H2O2 assay. MTT, wound healing assay and transwell matrigel invasion assay were used to detect the proliferation, migration and invasion potential of cancer cells. The expressions of uPA, E-cadherin and Glut-1 were examined using QT-PCR and western blot analysis at mRNA and protein levels. The activation of p-ERK, p-p38 and p-NF-κB were measured by western blot analysis. The results of the present study showed that resveratrol could significantly decrease high glucose-induced production of ROS and H2O2 in Panc-1 cells. Resveratrol was also able to inhibit high glucose-induced proliferation, migration and invasion of pancreatic cancer cells. High glucose-modulated expression of uPA, E-cadherin and Glut-1 were inhibited by resveratrol. In addition, high glucose-induced activation of ERK and p38 MAPK signaling pathways as well as the transcription factor NF-κB could also be suppressed by resveratrol. Furthermore, resveratrol was able to suppress H2O2-induced migration and invasion abilities of pancreatic cancer cells. Taken together, these data indicate that resveratrol plays an important role in suppressing hyperglycemia-driven ROS-induced pancreatic cancer progression by inhibiting the ERK and p38 MAPK signaling pathways, providing evidence that resveratrol might be a potential candidate for chemoprevention of pancreatic cancer.
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
Lei
L
Cao
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Xin
X
Chen
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
Xue
X
Xiao
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Qingyong
Q
Ma
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Wei
W
Li
D000111:Acetylcysteine / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048909:Diabetes Complications / Q000139:chemically induced / Q000188:drug therapy*; D005419:Flavonoids / Q000008:administration & dosage; D016166:Free Radical Scavengers / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D007093:Imidazoles / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D005419:Flavonoids; D016166:Free Radical Scavengers; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D013267:Stilbenes; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; C093642:SB 203580; D000077185:Resveratrol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine