1. Excess glucose induces hypoxia-inducible factor-1α in pancreatic cancer cells and stimulates glucose metabolism and cell migration
- Author
-
Feng Wang, Zhiwen Liu, Karl-Gösta Sundqvist, Johan Permert, Yijie Duan, Xiaohui Jia, and Huijie Xiao
- Subjects
Cancer Research ,medicine.medical_specialty ,Snf3 ,Cell Growth Processes ,Biology ,Carbohydrate metabolism ,Protein Serine-Threonine Kinases ,Adenosine Triphosphate ,Cell Movement ,Internal medicine ,Cell Line, Tumor ,medicine ,Extracellular ,Humans ,Glycolysis ,RNA, Messenger ,RNA, Small Interfering ,Pharmacology ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Cell migration ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,Pancreatic Neoplasms ,Endocrinology ,Glucose ,Oncology ,Hypoxia-inducible factors ,Hyperglycemia ,Molecular Medicine ,medicine.symptom ,Reactive Oxygen Species ,Intracellular ,Research Paper - Abstract
Pancreatic cancer patients frequently show hyperglycemia, but it is uncertain whether hyperglycemia stimulates pancreatic cancer cells. We have investigated whether excess glucose induces hypoxia-inducible factor-1α (HIF-1α) and stimulates glucose metabolism and cell migration in pancreatic cancer cells. We studied wild-type (wt) MiaPaCa2 pancreatic cancer cells and a MiaPaCa2 subline (namely si-MiaPaCa2) that had HIF-1α-specific small interfering RNA. Wt-MiaPaCa2 cells are known to be HIF-1α-positive in hypoxia and HIF-1α-negative in normoxia, whereas si-MiaPaCa2 cells are devoid of HIF-1α in both normoxia and hypoxia. We incubated these cells with different amounts of glucose and determined HIF-1α mRNA and protein by real-time polymerase chain reaction and western blotting. We determined glucose consumption, lactate production and intracellular hexokinase-II and ATP to assess glucose metabolisms and determined pyruvate dehydrogenase kinase-1, reactive oxygen species and fumarate to assess mitochondrial activities. Further, we studied cell migration using a Boyden chamber. Excess glucose (16.7−22.2mM) increased HIF-1α in hypoxic wt-MiaPaCa2 cells. HIF-1α expression increased ATP contents and inhibited mitochondrial activities. Extracellular glucose and hypoxia stimulated glucose metabolisms independent of HIF-1α. Excess glucose stimulated the migration of wt- and si-MiaPaCa2 cells in both normoxia and hypoxia. Thus, glucose stimulated cell migration independent of HIF-1α. Nevertheless, hypoxic wt-MiaPaCa2 cells showed greater migrating ability than their si-MiaPaCa2 counterparts. We conclude that (1) excess glucose increases HIF-1α and ATP in hypoxic wt-MiaPaCa2 cells, (2) extracellular glucose and hypoxia regulate glucose metabolisms independent of HIF-1α and (3) glucose stimulates cell migration by mechanisms that are both dependent on HIF-1α and independent of it.
- Published
- 2013