Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-08

AUTHORS

Hazem Ghebeh, Cynthia Lehe, Eman Barhoush, Khaldoon Al-Romaih, Asma Tulbah, Monther Al-Alwan, Siti-Faujiah Hendrayani, Pulicat Manogaran, Ayodele Alaiya, Taher Al-Tweigeri, Abdelilah Aboussekhra, Said Dermime

ABSTRACT

INTRODUCTION: B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients. METHODS: In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells. RESULTS: Among tested chemotherapeutic agents, doxorubicin was the most effective in downregulating cell surface expression of B7-H1 in vitro. These results were validated in vivo in a xenograft mouse model, as well as in murine heart tissue known to constitutively express B7-H1. The doxorubicin-dependent cell surface downregulation of B7-H1 was accompanied by an upregulation of B7-H1 in the nucleus. This re-distribution of B7-H1 was concurrent with a similar translocation of phosphorylated AKT to the nucleus. Inhibition of the PI3K/AKT pathway abrogated the doxorubicin-mediated nuclear up-regulation of B7-H1, suggesting an involvement of PI3K/AKT pathway in the nuclear up-regulation of B7-H1. Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells. The novel discovery of B7-H1 expression in the nuclei of breast cancer cells suggests that B7-H1 has functions other than inhibition of T cells. CONCLUSIONS: Our findings explain the previously reported immunomodulatory effect of anthracyclines on cancer cells, and provide a link between immunoresistance and chemoresistance. Finally these results suggest the use of dual combinatorial agents to inhibit B7-H1 beside chemotherapy, in breast cancer patients. More... »

PAGES

r48

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/bcr2605

DOI

http://dx.doi.org/10.1186/bcr2605

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008970191

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20626886


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