Mitogen-activated protein kinases and chemoresistance in pancreatic cancer cells.
نویسندگان
چکیده
BACKGROUND Chemoresistance is an important clinical problem in pancreatic cancer. As the mitogen-activated protein kinases (MAPKs) have been found to be involved in the development of chemoresistance in a variety of cancer cell lines, the aim of the current study was to assess the role and mechanism of MAPK signaling in mediating chemoresistance in pancreatic cancer cells. MATERIALS AND METHODS The effects of pharmacological inhibition of MAPKs on resistance of pancreatic cancer cells to apoptosis induced by treatment with chemotherapeutic drugs were analyzed. RESULTS Compared with parental cells, the activity of extracellular signal-regulated kinase (ERK) was elevated in all of the three chemoresistant sublines at basal conditions. Inhibition of the ERK pathway by PD98059 sensitized cells to 5-fluorouracil (5-FU), whereas cells became more resistant to Adriamycin (ADM; Meiji Seika, Tokyo, Japan) and gemcitabine (GEM). 5-FU induced apoptosis primarily via a caspase-8-dependent pathway, and ADM and GEM via caspase-9. PD98059 enhanced the activity of caspase-8 and inhibited the activation of caspase-9. In addition, PD98059 regulated the level of phospho-Bcl-2. CONCLUSIONS These data suggest that although constitutive activation of the ERK pathway might be a marker of chemoresistance, the effects of this pathway on chemoresistance of pancreatic cancer cells are drug dependent. This study also provides evidence for a possible link between the ERK pathway and activation of the caspases and Bcl-2.
منابع مشابه
Correction: DUSP1 Is a Novel Target for Enhancing Pancreatic Cancer Cell Sensitivity to Gemcitabine
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1) is a key negative regulator of mitogen activated protein kinases (MAPKs). Yet, DUSP1 is overexpressed in pancreatic cancer cells (P...
متن کاملEffects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies.
Pancreatic cancer is one of the most lethal cancers in the world, as it continues to be resistant to any therapeutic approaches. The high molecular weight glycoprotein mucin 4 (MUC4) is aberrantly expressed in pancreatic cancer and contributes to the regulation of differentiation, proliferation, metastasis, and the chemoresistance of pancreatic cancer cells. The absence of its expression in the...
متن کاملModulation of pancreatic cancer chemoresistance by inhibition of TAK1.
BACKGROUND TGF-β-activated kinase-1 (TAK1), a mitogen-activated protein kinase kinase kinase, functions in the activation of nuclear factor κB (NF-κB) and activator protein-1, which can suppress proapoptotic signaling pathways and thus promote resistance to chemotherapeutic drugs. However, it is not known if inhibition of TAK1 is effective in reducing chemoresistance to therapeutic drugs agains...
متن کاملNFκB-Associated Pathways in Progression of Chemoresistance to 5-Fluorouracil in an In Vitro Model of Colonic Carcinoma.
BACKGROUND Drug resistance to 5-fluorouracil (5-FU) is a major obstacle in colonic cancer treatment. Activation of nuclear factor-kappa B (NFκB), mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and protein kinase B (AKT) is thought to protect cancer cells against therapy-induced cytotoxicity. MATERIALS AND METHODS Using cytotoxicity assays and immunoblotting, the impact of inhibitor...
متن کاملMEK1 and MEK2 isoforms regulate distinct functions in pancreatic cancer cells.
The mitogen-activated protein kinase kinase 1/2 (MEK1/2) signalling pathway plays a central role in tumour progression. Small molecules that inhibit MEK1/2 are therefore considered attractive candidates for anti-cancer drugs. However, the exact contributions of MEK1 and MEK2 to the development of pancreatic cancer remain to be established. To differentiate the functions of MEK1 and MEK2 in a cu...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- The Journal of surgical research
دوره 136 2 شماره
صفحات -
تاریخ انتشار 2006