np-031112 and Pancreatic-Neoplasms

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant

Topics: Adenocarcinoma; Adenylate Kinase; Antineoplastic Agents; bcl-X Protein; Berberine; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Diabetes Mellitus; Dietary Supplements; Disease Progression; Doxorubicin; Female; Fluorouracil; Gemcitabine; Glycogen Synthase Kinase 3 beta; Glycolysis; Humans; Inhibitory Concentration 50; Malaria; MCF-7 Cells; Metformin; Molecular Targeted Therapy; Neoplasm Metastasis; Nitrophenols; Pancreatic Neoplasms; Piperazines; Protein Kinase Inhibitors; Signal Transduction; Sulfonamides; Thiadiazoles; Tumor Stem Cell Assay

To explore the role of POTEE in the malignant development of pancreatic cancer and the possible mechanism. POTEE levels in pancreatic cancer samples were detected. The relationship between POTEE level and clinical data of pancreatic cancer patients was analyzed. After knockdown of POTEE or treatment of the GSK-3β inhibitor, proliferative change in pancreatic cancer cells was assessed. Protein levels of vital genes in the PI3K/Akt/GSK-3β/β-catenin signaling influenced by POTEE were examined. POTEE was upregulated in pancreatic cancer samples. High level of POTEE indicated advanced tumor staging, large tumor size, and poor prognosis in pancreatic cancer patients. Knockdown of POTEE or treatment of Tideglusib remarkably attenuated proliferative ability in pancreatic cancer cells. Vital genes in the PI3K/Akt/GSK-3β/β-catenin signaling were downregulated by knockdown of POTEE. POTEE stimulates the proliferative ability in pancreatic cancer by activating the PI3K/Akt/GSK-3β/β-catenin signaling. High level of POTEE indicates advanced tumor staging, large tumor size and poor prognosis in pancreatic cancer patients.

Topics: Aged; Antigens, Neoplasm; Antineoplastic Agents; beta Catenin; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; Survival Analysis; Thiadiazoles; Tumor Burden