CRIPTO-1: a novel target for therapeutic intervention in human carcinoma.
Evidence suggests that CRIPTO-1 (CR-1) might be involved in the pathogenesis of human carcinoma. In the present study, we have screened the expression of CR-1 mRNA and protein in a wide panel of human cancer cell lines by using reverse transcriptase (RT)-PCR, real-time PCR and immunocytochemistry. Results of these experiments demonstrate that CR-1 is expressed in several, different carcinoma types. The anchorage-independent growth of colon, ovarian, lung and breast carcinoma cells was significantly inhibited by treatment with anti-CR-1 second generation antisense oligonucleotides. Similar results were obtained with anti-transforming growth factor alpha (TGF-alpha) and anti-amphiregulin (AR) antisense oligonucleotides. Treatment of carcinoma cells with CR-1 antisense oligonucleotides resulted in a significant reduction in the levels of expression of CR-1 mRNA and protein, and in the levels of activation of Akt. Finally, oral administration of either CR-1, AR or TGF-alpha antisense oligonucleotides produced a significant reduction in the growth of GEO colon carcinoma xenografts in nude mice that was associated with a reduction in the levels of expression of the target proteins. Taken together, these data strongly suggest that CR-1 might represent a novel target for therapeutic intervention in different carcinoma types.
Normanno
Nicola
N
Department of Experimental Oncology, INT-Fondazione Pascale, Via Mariano Semmola, I-80131 Naples, Italy. nicnorm@yahoo.com
De Luca
Antonella
A
Maiello
Monica R
MR
Bianco
Caterina
C
Mancino
Mario
M
Strizzi
Luigi
L
Arra
Claudio
C
Ciardiello
Fortunato
F
Agrawal
Sudhir
S
Salomon
David S
DS
D066258:Amphiregulin; D000818:Animals; D045744:Cell Line, Tumor; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D058851:GPI-Linked Proteins; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009369:Neoplasms / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C070636:TDGF1 protein, human; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor