Human immunodeficiency virus-1 Tat protein up-regulates interleukin-6 and interleukin-8 expression in human breast cancer cells.
OBJECTIVE
To examine whether HIV-1 Tat protein increases the metastatic potential of human breast cancer cells through induction of pro-inflammatory tumor microenvironment.


METHODS
Real-time RT-PCR and ELISA were employed to determine the mRNA and protein expression of IL-6 and IL-8 in highly metastatic human breast cancer cell line, MDA-MB-231. To investigate the transcriptional regulatory mechanisms of Tat-mediated up-regulation of IL-6 and IL-8, EMSA and reporter gene assay were carried out.


RESULTS
Exposure of MDA-MB-231 cells to Tat resulted in a significant and dose-dependent up-regulation of IL-6 and IL-8 mRNA and protein expression. HIV-1 Tat protein also markedly increased NF-kappaB DNA-binding activity and transactivation in MDA-MB-231 cells. Additionally, pretreatment with NF-kappaB inhibitors significantly attenuated the ability of Tat to up-regulate IL-6 and IL-8 expression. It was also found that exposure of MDA-MB-231 cells to Tat induced up-regulation of MMP-9 expression at both mRNA and protein levels.


CONCLUSIONS
These results suggest that HIV-1 Tat protein up-regulates expression of IL-6 and IL-8 in human breast cancer cells by NF-kappaB-dependent pathway. These data may contribute to exploration of the new molecular mechanisms leading to novel approaches for the therapeutic drug developments specifically targeted against the inflammatory pathways of breast cancer metastasis in AIDS patients.
Lee
Y W
YW
Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. ywlee@vt.edu
Hirani
A A
AA
Kyprianou
N
N
Toborek
M
M
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015696:Gene Products, tat / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; D014108:Tosylphenylalanyl Chloromethyl Ketone; D004247:DNA; D020780:Matrix Metalloproteinase 9