EphB Receptors Trigger Akt Activation and Suppress Fas Receptor-Induced Apoptosis in Malignant T Lymphocytes

Abstract

Treatment of hematopoietic malignancies often requires allogeneic bone marrow transplantation, and the subsequent graft-versus-leukemia response is crucial for the elimination of malignant cells. Cytotoxic T lymphocytes and NK cells responsible for the immunoelimination express Fas ligand and strongly rely on the induction of Fas receptor-mediated apoptosis for their action. Although cancer cells are removed successfully by graft-versus-leukemia reactions in myeloid malignancies, their efficiency is low in T cell leukemias. This may be partially because of the ability of malignant T cells to escape apoptosis. Our work shows that Eph family receptor EphB3 is consistently expressed by malignant T lymphocytes, most frequently in combination with EphB6, and that stimulation with their common ligands, ephrin-B1 and ephrin-B2, strongly suppresses Fas-induced apoptosis in these cells. This effect is associated with Akt activation and with the inhibition of the Fas receptor-initiated caspase proteolytic cascade. Akt proved to be crucial for the prosurvival response, because inhibition of Akt, but not of other molecules central to T cell biology, including Src kinases, MEK1 and MEK2, blocked the antiapoptotic effect. Overall, this demonstrates a new role for EphB receptors in the protection of malignant T cells from Fas-induced apoptosis through Akt engagement and prevention of caspase activation. Because Fas-triggered apoptosis is actively involved in the graft-versus-leukemia response and cytotoxic T cells express ephrin-Bs, our observations suggest that EphB receptors are likely to support immunoevasivenes of T cell malignancies and may represent promising targets for therapies, aiming to enhance immunoelimination of cancerous T cells.

Eph Receptor Signaling and Ephrins

“…EphB3 kinase activation can also inhibit Akt, which leads to suppression of non-small-cell lung cancer migration and metastasis, by promoting the assembly of a complex involving the EphB3 binding partner RACK1 (receptor for activated C-kinase 1), the serine/threonine phosphatase PP2A and Akt itself (Li et al 2012). However, Eph receptors can also activate Akt, for example in pancreatic cancer cells stimuated with ephrin-A1 (Chang et al 2008) or in malignant T lymphocytes where ephrin-B treatment suppresses apoptosis (Maddigan et al 2011). …”

The intrinsically kinase-inactive EPHB6 receptor predisposes cancer cells to DR5-induced apoptosis by promoting mitochondrial fragmentation

“…Previous reports, including the work of our group, have shown that some receptors of the EphB type suppress apoptotic responses triggered by death receptors [20-22, 31]. Since earlier work shows that EPHB6 often executes its responses through interactions with other EphB receptors [29, 32, 33], we examined if it also interferes with DR5-induced apoptosis in cancer cells.…”

“…Interestingly, we have not observed the pro-apoptotic effect of EPHB6 expression in our experiments with paediatric T-cell acute lymphoblastic leukaemia (T-ALL) cells (data not shown), which further confirms the specificity of our observations in TNBC cells and indicates that the pro-apoptotic EPHB6 action via DRP1 activation may be restricted to certain types of malignancies. This distinction could be due to the fact that EphB receptors, including EphB6, act in T-ALL cells in a completely different molecular context, which collectively allows them to activate the AKT kinase, initiating anti-apoptotic signaling and supporting cell survival [31]. …”

The Eph/Ephrin family in cancer metastasis: communication at the service of invasion

“…Upon stimulation by Ephrin-A1, EphA2 behaves as an upstream negative regulator of Akt, resulting in the inhibition of cell migration [111]. Interestingly, the PI3K/Akt and mitogenactivated protein kinase (MAPK) pathways are also important in other functions of Ephs and Ephrins such as cell death and autophagy [112][113][114][115], suggesting a complex but precise coordination. The analysis of transgenic mice models of mammary carcinomas where EphA2-deficiency and ErbB2 overexpression were combined, suggests that EphA2 cooperates with ErbB2 to promote tumor and metastatic progression.…”