Modulation of bcl-xL in tumor cells regulates angiogenesis through CXCL8 expression.
In this paper, we investigated whether bcl-xL can be involved in the modulation of the angiogenic phenotype of human tumor cells. Using the ADF human glioblastoma and the M14 melanoma lines, and their derivative bcl-xL-overexpressing clones, we showed that the conditioned medium of bcl-xL transfectants increased in vitro endothelial cell functions, such as proliferation and morphogenesis, and in vivo vessel formation in Matrigel plugs, compared with the conditioned medium of control cells. Moreover, the overexpression of bcl-xL induced an increased expression of the proangiogenic interleukin-8 (CXCL8), both at the protein and mRNA levels, and an enhanced CXCL8 promoter activity. The role of CXCL8 on bcl-xL-induced angiogenesis was validated using CXCL8-neutralizing antibodies, whereas down-regulation of bcl-xL through antisense oligonucleotide or RNA interference strategies confirmed the involvement of bcl-xL on CXCL8 expression. Transient overexpression of bcl-xL led to extend this observation to other tumor cell lines with different origin, such as colon and prostate carcinoma. In conclusion, our results showed that CXCL8 modulation by bcl-xL regulates tumor angiogenesis, and they point to elucidate an additional function of bcl-xL protein.
Giorgini
Simona
S
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Trisciuoglio
Daniela
D
Gabellini
Chiara
C
Desideri
Marianna
M
Castellini
Laura
L
Colarossi
Cristina
C
Zangemeister-Wittke
Uwe
U
Zupi
Gabriella
G
Del Bufalo
Donatella
D
D014408:Biomarkers, Tumor / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007797:Laminin; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D040081:Protein Array Analysis; D011509:Proteoglycans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; C508606:CXCL8 protein, human; D004338:Drug Combinations; D016209:Interleukin-8; D007797:Laminin; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D012333:RNA, Messenger; D051020:bcl-X Protein; C059485:matrigel; D003094:Collagen