Suppression of tumorigenicity of rhabdoid tumor derived G401 cells by the multivalent HB-19 pseudopeptide that targets surface nucleolin.
Several studies have indicated that the cell-surface expressed nucleolin is implicated in tumorigenesis and angiogenesis, and represents an important target for cancer therapy. Here we show that treatment of rhabdoid tumor derived G401 cells with a nucleolin antagonist, the HB-19 pseudopeptide, could restore contact inhibition, impair anchorage-independent growth, and suppress tumor development in nude mice. G401 cells grow without contact inhibition, which is an in vitro characteristic property of malignant tumor cells. At concentrations of HB-19 that does not affect cell viability and multiplication index, there is restoration of contact inhibition thus suggesting that HB-19 treatment causes reversion of the malignant phenotype. Accordingly, HB-19 pretreated G401 cells lose the capacity to form colonies in soft agar. When assayed for tumorigenicity in nude mice, only 50% of mice injected with HB-19 pretreated G401 cells developed tumors with the mean tumor weight of 0.32 g, compared to 100% of mice injected with control G401 cells with the mean tumor weight of 2.36 g. Interestingly, the restoration of contact inhibition in HB-19 treated G401 cells is concomitant with marked reduction of transcripts coding the Wilms' tumor 1 gene, matrix metalloproteinase-2, epithelial isoform of CD44, and vascular endothelial growth factor, whereas no apparent modification is detected for transcripts coding the proto-oncogene c-Myc, anti-apoptotic Bcl-2, pro-apoptotic Bax, tissue inhibitor of metalloproteinase TIMP-1, angiogenesis inhibitor TSP-1, and growth factor Midkine. These findings indicate that the molecular mechanism of action of HB-19 on such highly malignant rhabdoid tumor cells is associated with a selective inhibitory effect on the expression of genes implicated in tumorigenesis and angiogenesis.
CNRS-Université Paris Descartes, Unité Régulation de la Transcription de Maladies Génétique, 45 rue des Saints Pères, Paris Cedex 06, France.
Bernard
B
Krust
Diala
D
El Khoury
Calaiselvy
C
Soundaramourty
Isabelle
I
Nondier
Ara G
AG
Hovanessian
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D051379:Mice; D057786:Peptidomimetics / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D018335:Rhabdoid Tumor / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics; D000097796:Nucleolin
D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D020778:Matrix Metalloproteinase 2; D057786:Peptidomimetics; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D025721:WT1 Proteins; D000097796:Nucleolin