Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer

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.

Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway

“…We hypothesized that in the case of hyperglycemia complicated by neoplastic diseases, disease progression would be related to p38 MAPK signaling, including tumor cell proliferation and the EMT process. We found that HG promoted proliferation and enhanced invasiveness in pancreatic cancer cells, which was consistent with previous results [16, 17]. In addition, we discovered that HG induced p38 MAPK phosphorylation in pancreatic cancer cells, both in vitro and in vivo .…”

Identify potential clinical significance of long noncoding RNA forkhead box P4 antisense RNA 1 in patients with early stage pancreatic ductal adenocarcinoma

“…Numerous studies have shown that specific molecules can affect the tumorigenesis, progression, incursion as well as migration of pancreatic cancer by participating in the regulation of JAK/STAT pathway . MAPKKK cascade is the key molecule in the MAPK pathway, and MAPK pathway can be incorporated to control cell propagation, invasion, migration, apoptosis, tumorigenesis, and progression of pancreatic tumor, as well as chemotherapy response and clinical outcomes . For the two drugs that were identified in our current study, no previous studies have identified their functions on cancer treatment.…”

“…[41][42][43][44] MAPKKK cascade is the key molecule in the MAPK pathway, and MAPK pathway can be incorporated to control cell propagation, invasion, migration, apoptosis, tumorigenesis, and progression of pancreatic tumor, as well as chemotherapy response and clinical outcomes. [45][46][47][48][49][50][51] For the two drugs that were identified in our current study, no previous studies have identified their functions on cancer treatment. These two drugs as the targeted agents for pancreatic cancer remain to be confirmed by further research as well as clinical trials.…”

Curcumin inhibits H2O2-induced invasion and migration of human pancreatic cancer via suppression of the ERK/NF-κB pathway

“…Members of the MAPK family include extracellular signal-regulated kinase (ERK), c-jun NH-2 terminal kinase (JNK) and p38 MAPK. Our previous study demonstrated that a moderate amount of H 2 O 2 is able to promote pancreatic cancer invasion via the activation of the ERK and p38 MAPK signaling pathways (10). However, the ability of curcumin to inhibit the H 2 O 2 -induced progression of pancreatic cancer and the mechanisms related to this process have not been elucidated.…”

“…On one hand, an excessive amount of ROS production can kill cancer cells, whereas sublethal concentrations of ROS can stimulate tumor progression by promoting cell proliferation, survival, invasion and metastasis (9). Additionally, our previous study showed that H 2 O 2 (0-200 µM) could promote pancreatic cancer progression in a dose-dependent manner, while H 2 O 2 was cytotoxic at concentrations above 200 µM (10). A recent study showed that curcumin possesses a protective effect against the epithelial-mesenchymal transition (EMT) process in the prostate tumor-stromal interaction, which is dependent on its ability to ameliorate cancer-associated fibroblast-induced ROS production through the MAOA/mTOR/HIF-1α signaling pathway (11).…”