Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo

Brockschmidt, C.; Hirner, H.; Huber, N.; Eismann, T.; Hillenbrand, A.; Giamas, G.; Radunsky, B.; Ammerpohl, O.; Bohm, B.; Henne-Bruns, D.; Kalthoff, H.; Leithäuser, F.; Trauzold, A.; Knippschild, U.
June 2008
Gut;Jun2008, Vol. 57 Issue 6, p799
Academic Journal
Background: Pancreatic ductal adenocarcinomas (PDACs) are highly resistant to treatment due to changes in various signalling pathways. CK1 isoforms play important regulatory roles in these pathways. Aims: We analysed the expression levels of CK1 delta and epsilon (CK1δ/ε) in pancreatic tumour cells in order to validate the effects of CK1 inhibition by 3-[2,4,6- Itrimethoxyphenyl) methylidenyl]-indolin-2-one (lC261) on their proliferation and sensitivity to anti-CD95 and gemcitabine. Methods: CK1δ/ε expression levels were investigated by using western blotting and immunohistochemistry. Cell death was analysed by FACS analysis. Gene expression was assessed by real-time PCR and western blotting. The putative anti-tumoral effects of IC261 were tested in vivo in a subcutaneous mouse xenotransplantation model for pancreatic cancer. Results: We found that CK1δ/ε are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1δ/ε by IC261 reduced pancreatic tumour cell growth in vitro and in vivo. Moreover, IC261 decreased the expression levels of several anti-apoptotic proteins and sensitised cells to CD95-mediated apoptosis. However, IC261 did not enhance gemcitabine-mediated cell death either in vitro or in vivo. Conclusions: Targeting CK1 isoforms by IC261 influences both pancreatic tumour cell growth and apoptosis sensitivity in vitro and the growth of induced tumours in vivo, thus providing a promising new strategy for the treatment of pancreatic tumours.


Related Articles

  • Comparative proteomic analysis for the detection of biomarkers in pancreatic ductal adenocarcinomas. Qi, T.; Han, J.; Cui, Y.; Zong, M.; Liu, X.; Zhu, B. // Journal of Clinical Pathology;Jan2008, Vol. 61 Issue 1, p49 

    Aims: To search for novel potential protein biomarkers for the early detection and better intervention of pancreatic ductal adenocarcinoma (PDAC). Methods: Eight pairs of matched PDAC and non-cancerous pancreas tissues were profiled with two-dimensional electrophoresis; differentially expressed...

  • Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma. Chen, Ru; Dawson, David W; Pan, Sheng; Ottenhof, Niki A; de Wilde, Roeland F; Wolfgang, Christopher L; May, Damon H; Crispin, David A; Lai, Lisa A; Lay, Anna R; Waghray, Meghna; Wang, Shouli; McIntosh, Martin W; Simeone, Diane M; Maitra, Anirban; Brentnall, Teresa A // Laboratory Investigation (00236837);Jan2015, Vol. 95 Issue 1, p43 

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic...

  • Alteration of Cpn60 expression in pancreatic tissue of rats with acute pancreatitis. Xue-Li Li; Kun Li; Yong-Yu Li; Yan Feng; Qian Gong; Yan-Na Li; Xue-Jin Li; Chang-Jie Chen // Cell Stress & Chaperones;Summer2009, Vol. 14 Issue 2, p199 

    The expression of heat-shock protein 60 (also known as chaperonin 60, Cpn60) in experimental acute pancreatitis (AP) is considered to play an active role in the prevention of abnormal enzyme accumulation and activation in pancreatic acinar cells. However, there are controversial results in the...

  • PATTERNS OF MUCI TISSUE EXPRESSION DEFINED BY AN ANTI MUCI CYTOPLASMIC TAIL MONOCLONAL ANTIBODY IN BREAST CANCER. Croce, M. V.; Isla-Larrain, M.; Rua, C.; Rabassa, M.; Segal-Eiras, A. // Revista VacciMonitor (Vacunología y Temas Afines);Oct2002, Vol. 11 Issue 4, p1 

    MUC I is a highly glycosylated mucin with a large extracellular domain, a transmembrane fraction as well as a 72-aminoacid cytoplasmic tail (CT). The present research was developed to study the pattern of MUC 1 mucin expression in breast carcinoma with an anti MUCI cytoplasmic tail (CT) MAb...

  • The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition. Peddaboina, Chandler; Jupiter, Daniel; Fletcher, Steven; Yap, Jeremy L.; Rai, Arun; Tobin, Richard P.; Jiang, Weihua; Rascoe, Philip; Rogers, M. Karen Newell; Smythe, W. Roy; Cao, Xiaobo // BMC Cancer;2012, Vol. 12 Issue 1, p541 

    Background: It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survivalprotein in a variety of cell lineages and is critically regulated via...

  • HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells. Schüler, Susanne; Fritsche, Petra; Diersch, Sandra; Arlt, Alexander; Schmid, Roland M.; Saur, Dieter; Schneider, Günter // Molecular Cancer;2010, Vol. 9, p80 

    Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in...

  • Desmogleins as prognostic biomarkers in resected pancreatic ductal adenocarcinoma. Ormanns, Steffen; Altendorf-Hofmann, Annelore; Jackstadt, Rene; Horst, David; Assmann, Gerald; Zhao, Yue; Bruns, Christiane; Kirchner, Thomas; Knösel, Thomas; Knösel, Thomas // British Journal of Cancer;11/17/2015, Vol. 113 Issue 10, p1460 

    Background: Frequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell-cell...

  • Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40. Bergmann, F.; Aulmann, S.; Wente, M. N.; Penzel, R.; Esposito, I.; Kleeff, J.; Friess, H.; Schirmacher, P. // Journal of Clinical Pathology;Jun2006, Vol. 59 Issue 6, p580 

    Background: Pancreatic ductal adenocarcinoma (PDAC) rarely affects people under 40. Objectives: To determine whether the clinical, pathomorphological and genetic features of PDAC occurring in young patients (≼ 40 years) differ from those in elderly patients. Methods: Clinical and...

  • High Expression of CX3CL1/CX3CR1 Axis Predicts a Poor Prognosis of Pancreatic Ductal Adenocarcinoma. Xu, Xianhui; Wang, Yang; Chen, Jinshui; Ma, Hongyun; Shao, Zhuo; Chen, Haitao; Jin, Gang // Journal of Gastrointestinal Surgery;Aug2012, Vol. 16 Issue 8, p1493 

    Background: CX3CL1 is a member of the chemokine family, and its receptor, CX3CR1, is expressed in pancreatic ductal adenocarcinoma. However, it is unclear whether there is a correlation between the expression of CX3CL1/CX3CR1 axis and the prognosis of patients with pancreatic ductal...


Read the Article


Sign out of this library

Other Topics