CPT1B maintains redox homeostasis and inhibits ferroptosis to induce gemcitabine resistance via the KEAP1/NRF2 axis in pancreatic cancer.

BACKGROUND: Although we have made progress in treatment and have increased the 5-year survival by ≤30% in pancreatic cancer, chemotherapy resistance remains a major obstacle. However, whether reprogrammed lipid metabolism contributes to chemoresistance still needs to be further studied. METHODS: Gene expression was determined using Western blotting and quantitative reverse transcription polymerase chain reaction. Cell cloning formation assay, Cell Counting Kit-8, EdU assay, wound healing assay, transwell assay, and flow cytometry were used to detect apoptosis, cell proliferation capacity, migration capacity, and cytotoxicity of gemcitabine. Confocal fluorescence microscopy, transmission electron microscopy, etc., were used to detect the changes in intracellular reactive oxygen species, glutathione, lipid peroxidation level, and cell morphology. An animal study was performed to evaluate the effect of CPT1B knockdown on tumor growth and gemcitabine efficacy. RESULTS: In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of pancreatic cancer cells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT1B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma. CONCLUSION: CPT1B may act as a promising target in treating patients with gemcitabine-resistant pancreatic ductal adenocarcinoma .

Mechanical Regulation of Redox Balance via the Induction of the PIN1/NRF2/ARE Axis in Pancreatic Cancer.

Pancreatic cancer is one of the most lethal malignancies. Desmoplastic stroma and metabolic reprogramming are two hallmarks of pancreatic cancer that support its malignant biological behaviors. However, the underlying mechanism by which the stroma maintain the redox balance remains unclear in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrated that the physical properties of the stroma could regulate the expression of PIN1 in pancreatic cancer cells. Moreover, we found that hard matrix-cultured pancreatic cancer cells induced the upregulation of PIN1 expression. Since PIN1 maintained redox balance via synergistic activation of NRF2 transcription, PIN1 promoted the expression of NRF2 to induce the expression of intracellular antioxidant response element (ARE)-driven genes. Consequently, the antioxidant stress ability of PDAC was increased, and the intracellular level of reactive oxygen species (ROS) was decreased. Thus, PIN1 is expected to be an important target for the treatment of PDAC, especially PDAC with an exuberant desmoplastic stroma.

Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.

Analysis of 4 children with pancreatic solid pseudopapillary neoplasm treated by total laparoscopic pancreaticoduodenectomy / 中华胰腺病杂志

Objective To investigate the application and surgical experience of total laparoscopic pancreaticoduodenectomy ( TLPD ) in treating children with solid pseudopapillary neoplasm ( SPN ) of pancreas. Methods Clinical data 4 children with SPN who underwent TLPD in Jilin University First Hospital from April 2017 to June 2018 were retrospectively analyzed. Results Among the 4 children, a case was male and 3 cases were female. Their age ranged from 9 to 14 year-old, the height ranged from 1. 2 to 1. 7 meters, and body weight ranged from 30 to75 kg. All patients complained of upper abdominal pain, one child had nausea and vomiting, and one child had abdominal mass. All patients underwent abdominal enhanced CT scan before operation, which showed a mass-like low-density shadow or mixed density shadow in the pancreatic head, with slightly uneven enhancement or no obvious enhancement. All 4 patients underwent TLPD, and the operation was successful without conversion to open surgery. The duration of operation time ranged from 250 to 365 minutes, the intraoperative blood loss ranged from 80 to 120 ml, the tumor size ranged from 4 to 8 cm, and the hospital stay ranged from 10 to 22 days. One patient developed grade B pancreatic fistula after surgery and was cured after conservative treatment. Pathological examinations of all patients confirmed the diagnosis of pancreatic SPN. All patients were followed up until February 2019, and no significant discomfort was observed and no recurrence or metastasis was found. Conclusions TLPD was safe and feasible in children in relatively large pancreatic surgery centers with extensive laparotomy and TLPD experience.

Analysis of 4 children with pancreatic solid pseudopapillary neoplasm treated by total laparoscopic pancreaticoduodenectomy / 中华胰腺病杂志

Objective@#To investigate the application and surgical experience of total laparoscopic pancreaticoduodenectomy (TLPD) in treating children with solid pseudopapillary neoplasm (SPN) of pancreas.@*Methods@#Clinical data 4 children with SPN who underwent TLPD in Jilin University First Hospital from April 2017 to June 2018 were retrospectively analyzed.@*Results@#Among the 4 children, a case was male and 3 cases were female. Their age ranged from 9 to 14 year-old, the height ranged from 1.2 to 1.7 meters, and body weight ranged from 30 to75 kg. All patients complained of upper abdominal pain, one child had nausea and vomiting, and one child had abdominal mass. All patients underwent abdominal enhanced CT scan before operation, which showed a mass-like low-density shadow or mixed density shadow in the pancreatic head, with slightly uneven enhancement or no obvious enhancement. All 4 patients underwent TLPD, and the operation was successful without conversion to open surgery. The duration of operation time ranged from 250 to 365 minutes, the intraoperative blood loss ranged from 80 to 120 ml, the tumor size ranged from 4 to 8 cm, and the hospital stay ranged from 10 to 22 days. One patient developed grade B pancreatic fistula after surgery and was cured after conservative treatment. Pathological examinations of all patients confirmed the diagnosis of pancreatic SPN. All patients were followed up until February 2019, and no significant discomfort was observed and no recurrence or metastasis was found.@*Conclusions@#TLPD was safe and feasible in children in relatively large pancreatic surgery centers with extensive laparotomy and TLPD experience.