Superoxide-Generating Nox5α Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells in vitro.To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5␣ expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5␣ variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5␣ by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5␣ is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development. IMPORTANCEHTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5␣ is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5␣ is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5␣-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5␣-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox-dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5␣ serves as a potential molecular target to treat HTLV-1-related leukemia.H uman T-cell leukemia virus type 1 (HTLV-1) is the first human oncogenic retrovirus shown to be etiologically associated with adult T-cell leukemia (ATL) (1, 2). ATL has a poor prognosis because of its resistance to conventional chemotherapy, and no effective therapy is currently available for ATL. HTLV-1 infects and transforms human peripheral blood T cells in vitro (3,4), but the precise mechanism of HTLV-1 transformation of T cells and the development of ATL after HTLV-1 infection are not fully understood. A HTLV-1 genome pX region-encoded protein, Tax, is thought to play a central role in activation, proliferation, and transfor...

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