Resistance of Sézary cells to TNF‐α‐induced apoptosis is mediated in part by a loss of TNFR1 and a high level of the IER3 expression

Abstract

Failure to execute an apoptotic program is one of the critical steps and a common mechanism promoting tumorogenesis. Immediate early responsive gene 3 (IER3) has been shown to be upregulated in several cancers. IER3 is a stress induced gene, which upregulation leads to reduction in production of reactive oxygen species (ROS) protecting malignant cells from apoptosis. We observed that malignant lymphocytes from patients with Sézary syndrome (SzS) were resistant to pro-apoptotic dose of tumor necrosis factor-α (TNF-α). The aim of this study was to investigate the role of IER3 in the mechanism of such resistance. CD4+ CD26− lymphocytes from the peripheral blood of patients with SzS and healthy controls were negatively selected using CD4 and CD26 magnetic beads and analyzed for expression of TNFR1, TNFR2, IER3 expression, and ROS production in response to TNF-α at an apoptotic dose. Sézary cells with a higher level of IER3 expression retained their viability to TNF-α. IER3 upregulation correlated with a decrease level of intracellular ROS and low TNFR1 expression on malignant cells. Targeting IER3 could be of interest for the development of future therapeutic strategies for patients with SzS.

Expression of IER3 in Primary Hepatocarcinoma: Correlation with Clinicopathological Parameters

“…It is reported that IER3 upregulation is correlated with a decrease level of intracellular ROS and low TNFR1 expression on malignant lymphocytes. Targeting IER3 could be of interest for the development of future therapeutic strategies for patients with Sezary syndrome (Akilov et al, 2012).…”

Construction and Expression of an Eukaryotic Expression Vector Containing the IER3 Gene

“…There is three hypothesis that was gotten scholars' consensus. The fist one is that IER3 gene may combine FIFOATP complex in mitochondria, which regulates the level of the ATP and active oxygen free radicals (ROS) whose role is very important in cancer cells' apoptosis (Akilov et al, 2012). Another mechanism is involved in cellular immunity.…”

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

“…Positive IER3 expression is associated with good prognosis in ovarian cancer, where IER3 functions as a proapoptotic factor to restrict tumor growth (18,19). On the contrary, a high level of IER3 expression appears to link poor survival of patients with multiple myeloma (20)(21)(22)(23)(24)(25), Sézary syndrome (26)(27)(28), and breast cancer (29), in part due to a prosurvival effect of IER3 on cancer cells. In myelodysplastic syndromes, IER3 expression increases gradually with disease development toward acute myeloid leukemia (23,24).…”

“…However, since IER3 is a multifunctional factor, additional work is required to define whether this protein exerts additional protumoral effects through interference with other signaling pathways, in particular NF-κB (10,48) and PI3K/AKT (17). Similarly, with respect to cellular mechanisms, it is possible that this protein additionally modulates pancreatic carcinogenesis by modifying immunological responses (49,50) and apoptosis (10,11,28,51), which are well-characterized players in the process of pancreatic cell transformation. Thus, our present findings not only extend the existing knowledge in the field, but also generate the rational for additional studies.…”