Abstract
The chemokine receptor CXCR4 plays an integral role in the development of highly metastatic breast cancer and in the pathogenesis of chronic HIV infection. In this study, we compared the effects of CXCR4 antagonists on apoptosis induction in hematopoietic cells and in tumor cells. We incubated cells expressing CXCR4 with a series of CXCR4 antagonists and subsequently exposed the cultures to a pro-apoptotic peptide derived from the HIV-1 Nef protein (NefM1). The NefM1 peptide contains residues 50–60 of Nef and was previously shown to be the sequence necessary for Nef to initiate the apoptotic program through CXCR4 signaling. We found that several of the compounds studied potently blocked Nef-induced apoptosis in Jurkat T-lymphocyte cells. Interestingly, many of the same compounds selectively triggered apoptosis in MDA-MB-231 breast cancer cells, in some cases at sub-nanomolar concentrations. None of the compounds were toxic to lymphocyte, monocyte or macrophage cells, suggesting that aggressive breast cancer carcinomas may be selectively targeted and eliminated using CXCR4-based therapies without additional cytotoxic agents. Our results also demonstrate that not all CXCR4 antagonists are alike and that the observed anti-Nef and pro-apoptotic effects are chemically tunable. Collectively, these findings suggest our CXCR4 antagonists have promising clinical utility for HIV or breast cancer therapies as well as being useful probes to examine the link between CXCR4 and apoptosis.
Highlights
CXCR4 is a G-protein coupled receptor charged with a multitude of biological functions including T-cell activation [1], chemotaxis [2], vascularization [3], and cellular proliferation [4]
Previous studies in our laboratory have shown that HIV1 Nef protein is present in the plasma of HIV-1 infected patients in amounts sufficient to induce apoptosis; that the apoptotic activity of the HIV-1 Nef protein can be localized in two 10-amino acid regions called Motif 1 (M1) and Motif 2 (M2) and that the extracellular Nef protein targets CD4+ T lymphocytes for apoptosis by interacting with the chemokine receptor CXCR4 [14,15,16,17]
We previously reported that the full length Nef protein and Nef peptides containing residues 50–60 bind to CXCR4 and initiate the apoptotic program in CD4+ T cells which may contribute to the pathogenesis of AIDS in vivo [14, 15]
Summary
CXCR4 is a G-protein coupled receptor charged with a multitude of biological functions including T-cell activation [1], chemotaxis [2], vascularization [3], and cellular proliferation [4]. CXCR4 promotes neoplastic transformations in various cell types to facilitate cellular proliferation, invasiveness, and survival that results in poor prognosis www.oncotarget.com and enhanced morbidity [9]. It plays a prominent role in HIV-1 infection and interacts with several HIV1 viral proteins including gp120, Tat, and Nef [10,11,12,13]. CXCR4 antagonists are known to block entry of CXCR4-tropic HIV-1 viruses into cells, it remains unclear if these compounds have the capacity to curb Nefinduced apoptosis
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