Abstract
BackgroundDiabetes is recognized to be a risk factor of pancreatic cancer, but the mechanism has not been fully elucidated. Sterol regulatory element binding protein 1 (SREBP1) is an important transcription factor involved in both lipid metabolism and tumor progression. However, the relationship between high glucose microenvironment, SREBP1 and pancreatic cancer remains to be explored.MethodsClinical data and surgical specimens were collected. Pancreatic cancer cell lines BxPc-3 and MiaPaCa-2 were cultured in specified medium. Immunohistochemistry (IHC) and western blotting were performed to detect the expression of SREBP1. MTT and colony formation assays were applied to investigate cell proliferation. Immunofluorescence, mRFP-GFP adenoviral vector and transmission electron microscopy were performed to evaluate autophagy. We used streptozotocin (STZ) to establish a high glucose mouse model for the in vivo study.ResultsWe found that high blood glucose levels were associated with poor prognosis in pancreatic cancer patients. SREBP1 was overexpressed in both pancreatic cancer tissues and pancreatic cancer cell lines. High glucose microenvironment promoted tumor proliferation, suppressed apoptosis and inhibited autophagy level by enhancing SREBP1 expression. In addition, activation of autophagy accelerated SREBP1 expression and suppressed apoptosis. Moreover, high glucose promotes tumor growth in vivo by enhancing SREBP1 expression.ConclusionOur results indicate that SREBP1-autophagy axis plays a crucial role in tumor progression induced by high glucose microenvironment. SREBP1 may represent a novel target for pancreatic cancer prevention and treatment.
Highlights
Diabetes is recognized to be a risk factor of pancreatic cancer, but the mechanism has not been fully elucidated
High glucose promotes proliferation and suppresses apoptosis by upregulating Sterol regulatory element binding protein 1 (SREBP1) our results indicate that the glucose supply is of vital importance to the processes of proliferation and apoptosis, it is unclear whether it functions through SREBP1 regulation
High glucose regulates autophagy by upregulating SREBP1 expression Our results indicated that high glucose is able to regulate SREBP1 expression and autophagy, though it had not yet been elucidated whether high glucose controls the level of autophagy by regulating SREBP1
Summary
Diabetes is recognized to be a risk factor of pancreatic cancer, but the mechanism has not been fully elucidated. The relationship between high glucose microenvironment, SREBP1 and pancreatic cancer remains to be explored. Much remains to be learned about the tumorigenesis and tumor progression mechanisms mediated by high glucose microenvironment. Cancer cells require a considerable nutrient supply for their rapid growth, and glucose has been proven to be their main source of energy [16]. Due to its extensive desmoplastic reaction, PC is characterized by hypovascularization [17], and pancreatic cancer cells are more dependent on a high level of glycolysis rather than oxidative phosphorylation [17,18,19]. Autophagy is activated to maintain cell survival when the energy supply is insufficient [21]. In PC, autophagy is thought to be a protective factor during tumorigenesis [21] as well as a factor contributing to proliferation [22]
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