HBZ Stimulates Brain-Derived Neurotrophic Factor/TrkB Autocrine/Paracrine Signaling To Promote Survival of Human T-Cell Leukemia Virus Type 1-Infected T Cells

Abstract

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal proliferation, survival, and plasticity. These effects occur through autocrine and paracrine signaling events initiated by interactions between secreted BDNF and its high-affinity receptor, TrkB. A BDNF/TrkB autocrine/paracrine signaling loop has additionally been implicated in augmenting the survival of cells representing several human cancers and is associated with poor patient prognosis. Adult T-cell leukemia (ATL) is a fatal malignancy caused by infection with the complex retrovirus human T-cell leukemia virus type 1 (HTLV-1). In this study, we found that the HTLV-1-encoded protein HBZ activates expression of BDNF, and consistent with this effect, BDNF expression is elevated in HTLV-1-infected T-cell lines compared to uninfected T cells. Expression of TrkB is also higher in HTLV-1-infected T-cell lines than in uninfected T cells. Furthermore, levels of both BDNF and TrkB mRNAs are elevated in peripheral blood mononuclear cells (PBMCs) from ATL patients, and ATL patient sera contain higher concentrations of BDNF than sera from noninfected individuals. Finally, chemical inhibition of TrkB signaling increases apoptosis in HTLV-1-infected T cells and reduces phosphorylation of glycogen synthase kinase 3␤ (GSK-3␤), a downstream target in the signaling pathway. These results suggest that HBZ contributes to an active BDNF/TrkB autocrine/paracrine signaling loop in HTLV-1-infected T cells that enhances the survival of these cells. IMPORTANCEInfection with human T-cell leukemia virus type 1 (HTLV-1) can cause a rare form of leukemia designated adult T-cell leukemia (ATL). Because ATL patients are unresponsive to chemotherapy, this malignancy is fatal. As a retrovirus, HTLV-1 integrates its genome into a host cell chromosome in order to utilize host factors for replication and expression of viral proteins. However, in infected cells from ATL patients, the viral genome is frequently modified to block expression of all but a single viral protein. This protein, known as HBZ, is therefore believed to modulate cellular pathways necessary for the leukemic state and the chemotherapeutic resistance of the cell. Here we provide evidence to support this hypothesis. We found that HBZ promotes a BDNF/TrkB autocrine/paracrine signaling pathway that is known to enhance the survival and chemotherapeutic resistance of other types of cancer cells. It is possible that inhibition of this pathway may improve treatments for ATL.

Human T-cell lymphotropic virus type 1 and its oncogenesis

“…Interestingly, HBZ inhibits the p53-enhancing function of ATF3, which is deleterious to ATL development, but does not hinder the cell proliferative function of ATF3 in ATL cells [91] . Two independent studies have shown that HBZ also employs certain autocrine/paracrine pathways to enhance ATL cell proliferation [92,93] . HBZ suppresses the canonical Wnt pathway, but it enhances the proliferation and migration of ATL cells by increasing expression of the noncanonical Wnt5a [92] .…”

“…HBZ suppresses the canonical Wnt pathway, but it enhances the proliferation and migration of ATL cells by increasing expression of the noncanonical Wnt5a [92] . In addition, HBZ upregulates the expression of brain-derived neurotropic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), which further promotes ATL cell proliferation [93] . HBZ-induced double-strand breaks (DSBs) are dependent on several microRNAs (miRNA) that are HBZ-inducible, such as miR17 and miR21 [94] .…”

BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells

“…The sub-G1 accumulation observed in cell cycle analyses may be related to apoptotic cells, which can be identified on DNA frequency histograms as cells with fractional DNA content (Kajstura et al 2007). A previous report using leukemia cells found apoptosis and reduction of GSK-3β phosphorylation after ANA-12 treatment (Polakowski et al 2014). In neurons, GSK-3β activation counteracts the effects of BDNF, and specific downstream signaling of TrkB phosphorylation pathway converge to the inactivation of GSK-3β (Phukan et al 2010).…”

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

“…We also observed an 1.8-fold change increase in TUBB3 mRNA levels in UW228 cells (Figure 6E), however, there were no differences in the protein content of TUBB3 (Figure 6F, 6G). These findings (Polakowski et al, 2014;Sinkevicius et al, 2014;Heinen et al, 2016;Pinheiro et al, 2017;Moriwaki et al, 2018). The present study is the first to evaluate the antitumoral effects of ANA-12 in a pediatric cancer animal model.…”