Effect of octreotide on apoptosis-related proteins in rat Kupffer cells: a possible anti-tumour mechanism.
BACKGROUND
Octreotide may prolong survival in patients with hepatocellular carcinoma, through an as yet unidentified mechanism. Kupffer cells play a key role in antitumour activity. Kupffer cell apoptosis is of major importance for the maintenance of this antitumour activity.


METHODS
We studied the in vitro effects of octreotide in the RNA expression of apoptotic and antiapoptotic proteins in isolated rat Kupffer cells, before and after exposure to lipopolysaccharide (LPS). Apoptotic and antiapoptotic gene expression was assessed using a semi-quantitative multiplex RT-PCR measuring bax, bcl-xS, bcl-2 and bcl-xL. LICE (caspase-3) mRNA was used as a measure of apoptosis.


RESULTS
Unstimulated Kupffer cells exhibited increased proapoptotic gene expression in a time-dependent manner, paralleled by a similar increase of LICE. LPS stimulation decreased the expression of proapoptotic bax and bcl-xS mRNA without effecting the antiapoptotic proteins. A decrease of LICE expression became significant at 48 hours. Octreotide showed a reduction of proapoptotic proteins, accompanied by an early increase and a late reduction of antiapoptotic proteins and a net decrease of LICE expression. A combination of LPS and octreotide produced a similar effect with the exception of a late increase of LICE expression, probably caused by a late increase of bax and bcl-xS.


CONCLUSIONS
LPS and octreotide reverse the observed increased apoptosis of cultured Kupffer cells by influencing both proapoptotic and antiapoptotic proteins. Therefore, the antitumour effect of octreotide in hepatocellular carcinoma may, in part, be explained by its antiapoptotic effect on Kupffer cells.
Xidakis
Costas
C
Department of Gastroenterology, Faculty of Medicine, University of Crete, Heraklion, Greece.
Kolios
George
G
Valatas
Vassilis
V
Notas
George
G
Mouzas
Ioannis
I
Kouroumalis
Elias
E
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015282:Octreotide / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D018931:Antineoplastic Agents, Hormonal; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015282:Octreotide