Abstract
Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contributes to their enhanced metastatic behavior. Here we show that hyperglycemia increases the hydrogen peroxide (H2O2) concentration through up-regulation of manganese superoxide dismutase (SOD2) expression, which further activates the ERK and p38 MAPK pathways, as well as the transcription factors NF-κB and AP-1, in a time-dependent manner. The invasion of pancreatic cancer cells resulting from the activation of the H2O2/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2. In addition, streptozotocin-treated diabetic nude mice exhibit a stronger tumor invasive ability in renal capsule xenografts which could be suppressed by PEG-CAT treatment. Furthermore, the integrated optical density (IOD) of SOD2 and uPA stainings is higher in the tumor tissues of pancreatic cancer patients with diabetes compared with pancreatic cancer patients with euglycemia. Taken together, our results demonstrate that hyperglycemia enhances cell invasive ability through the SOD2/H2O2/MAPK axis in human pancreatic cancer. Thus, SOD2/H2O2/MAPK axis may represent a promising therapeutic target for pancreatic cancer patients combined with diabetes mellitus.
Highlights
As the fourth leading cause of cancer death worldwide, pancreatic cancer (PC) is an aggressive malignant disease with dismal prognosis, partially due to the lack of early diagnosis and treatment options [1]
Our results show that the levels of H2O2 in BxPC-3 and Panc-1 cells are upregulated in response to high glucose concentrations in comparison to normal physiological glucose level (5.5 mM glucose) in both time-dependent and dose-dependent manners
Hyperglycemia is correlated with increased expression levels of SOD2 and urokinase plasminogen activator (uPA) in the tissue specimens obtained from PC patients
Summary
As the fourth leading cause of cancer death worldwide, pancreatic cancer (PC) is an aggressive malignant disease with dismal prognosis, partially due to the lack of early diagnosis and treatment options [1]. Surgery remains the only way to cure this severe disease, more than 80% of patients cannot be considered for surgical resection at the time of initial diagnosis [2]. Clinical data have clearly indicated that patients with DM can aggravate the progression of PC. Preoperative DM decreased both the rates of disease-free survival and overall survival for patients undergoing resection for PC [8]. Our own study demonstrated that DM enhances perineural invasion in PC patients and aggravates a poor prognosis [9]. Little is known about the specific mechanism regarding the relationship between PC progression and DM
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