Endo Masafumi, Inatsu Asako, Hashimoto Koji, Takamune Nobutoki, Shoji Shozo, Misumi Shogo
Department of Pharmaceutical Biochemistry, Faculty of Medical and Pharmaceutical Science, Kumamoto University, Kumamoto, Japan.
Curr HIV Res. 2008 Jan;6(1):34-42. doi: 10.2174/157016208783571991.
HIV-1 infection results in an increased risk of malignancy as well as immune suppression. However, analyses of cancer incidence in chronically immunosuppressed transplant recipients and HIV-infected person have demonstrated an unexpected low incidence of certain types of cancer, such as breast cancers, and the mechanism behind this remains unclarified. In this study, we show that most breast cancer cell lines express CXCR4 but are not susceptible to HIV-1 infection. The apoptosis of breast cancer cells is induced by HIV-1 in a viral-dose- and time-dependent manner without productive infection. The apoptosis is induced by R5X4 and X4 HIV-1 but not by R5 HIV-1, and is inhibited by an anti-CXCR4 antibody, an anti-gp120 antibody, AMD3100, or pertussis toxin. The apoptosis is mediated via CXCR4 in breast cancer cells that exhibit conformational heterogeneity in comparison with CXCR4 in T-cells. Furthermore, the gp120 mutant (E370R) with a low CD4 binding ability can specifically induce apoptosis in breast cancer cells but not in T-cells. Taken together, these results indicate that HIV-1 and gp120 can induce breast cancer cell apoptosis through gp120-CXCR4 interaction without a CD4-induced conformational change of gp120, and may lead to a novel HIV-1-based therapy for breast cancer.
HIV-1感染会增加患恶性肿瘤以及免疫抑制的风险。然而，对长期免疫抑制的移植受者和HIV感染者的癌症发病率分析显示，某些类型的癌症，如乳腺癌的发病率出人意料地低，其背后的机制仍不清楚。在本研究中，我们发现大多数乳腺癌细胞系表达CXCR4，但对HIV-1感染不敏感。HIV-1以病毒剂量和时间依赖性方式诱导乳腺癌细胞凋亡，而无 productive 感染。R5X4和X4型HIV-1可诱导凋亡，而R5型HIV-1则不能，抗CXCR4抗体、抗gp120抗体、AMD3100或百日咳毒素可抑制凋亡。与T细胞中的CXCR4相比，乳腺癌细胞中表现出构象异质性的CXCR4介导了凋亡。此外，具有低CD4结合能力的gp120突变体（E370R）可特异性诱导乳腺癌细胞凋亡，而不能诱导T细胞凋亡。综上所述，这些结果表明，HIV-1和gp120可通过gp120-CXCR4相互作用诱导乳腺癌细胞凋亡，而无需gp120的CD4诱导构象变化，这可能会导致一种基于HIV-1的新型乳腺癌治疗方法。
