Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

Abstract

Ras signaling pathways play an important role in cellular proliferation and survival, and inappropriate activation of Ras frequently results in cell transformation and cancer. Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of the adult T-cell leukemia/lymphoma (ATLL), a severe malignancy that has a poor prognosis and exhibits resistance to conventional chemotherapy. Although the mechanisms involved in cell transformation by HTLV-1 have not been completely clarified, it is generally thought that Tax plays a pivotal role in the process. We have previously proposed that a functionally active Ras protein is needed for efficient anti-apoptotic activity of Tax. In this study we report data indicating that the apoptotic resistance of cells expressing Tax, constitutively or transiently, is linked to the intracellular levels of Ras-GTP. Indeed, we found that Tax-positive cells have a high content of active Ras, and that inhibition of Ras signaling, using the antagonist farnesyl thyosalicylic acid (FTS), increases their sensitivity to apoptosis. FTS treatment was also accompanied by a decrease in ERK, but not Akt, phosphorylation. Thus, all together our data suggest that the interaction between Tax and Ras could be important to ATLL pathogenesis, and indicate Ras as a possible target for therapeutic intervention in ATLL patients.

T‐cell lymphomas associated gene expression signature: Bioinformatics analysis based on gene expression Omnibus

“…32 Activation of JAK/STAT, NF-kappa B, and Ras signaling pathways was examined in T-cell lymphoma. 20,33 The above results confirmed that our bioinformatics analysis was credible and reliable.…”

Lack of KRAS Gene Mutations in Chronic Myeloid Leukemia in Iran

“…For example failing or losing response to imatinib drug in CML patients may be due to RAS mutation (Pavlu et al, 2007). Therefore, detection and controlling the expression of this pathway could improve chemotrapy treatment in leukemia (Steelman et al, 2011;Stoppa et al, 2012). So, in this study we assessed the frequency of KRAS mutation (codon 12, 13) in CML.…”

Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

“…In addition, Tax is shown to induce the processing of p100 to yield p52 for the activation of the noncanonical NF-B pathway (19,20). The constitutive activation of NF-B not only promotes the survival and transformation of HTLV-1-infected cells (21,22) but also induces the resistance of these cells to many apoptosis inducers, including gamma irradiation, cisplatin, Fas ligand (FasL), and tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) (23)(24)(25)(26)(27).…”