PKCmu prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells.
Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumour progression. Protein kinases C (PKC) have been shown to be important in the regulation of proliferation and apoptosis. In this report, we investigated the role of the PKC-like kinase PKCmu in the control of these processes in pancreatic adenocarcinoma cells. We demonstrate that in these cells, PKCmu expression strongly correlates with resistance to CD95-induced apoptosis. Inhibition of PKCmu with Goe6983 sensitized resistant cells to CD95-induced apoptosis. In CD95-sensitive Colo357 cells, forced overexpression of PKCmu strongly reduced CD95-mediated apoptosis, an effect that could be reversed by pretreatment with Goe6983. In addition, PKCmu overexpression led to a strongly enhanced cell growth and to a significant increase of telomerase activity. In an attempt to identify the signalling pathways affected by PKCmu, we identified the antiapoptotic proteins c-FLIPL and survivin to be strongly upregulated in PKCmu overexpressing cells. Immunohistochemical analysis of pancreatic tumour tissue of 48 patients and 10 normal pancreatic tissues revealed marked overexpression of PKCmu in tumours. In conclusion, we showed that PKCmu controls proliferative, as well as anti-apoptotic, signalling pathways and therefore plays an important role in acquiring the malignant phenotype of pancreatic tumours.
Trauzold
Anna
A
Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, Christian-Albrechts-University, Arnold-Heller-Str7, D-24105 Kiel, Germany.
Schmiedel
Stefan
S
Sipos
Bence
B
Wermann
Hendrik
H
Westphal
Sabine
S
Röder
Christian
C
Klapper
Wolfram
W
Arlt
Alexander
A
Lehnert
Lasse
L
Ungefroren
Hendrik
H
Johannes
Franz-Josef
FJ
Kalthoff
Holger
H
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D000077022:Survivin; D019098:Telomerase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D019014:fas Receptor; C089212:protein kinase D; D011493:Protein Kinase C; D019098:Telomerase