Activation of PKC-δ in HTLV-1-infected T cells

Abstract

Protein kinase C (PKC)-δ is a member of the PKC family. It has been implicated in tumor suppression as well as survival of various cancers. The aggressive malignancy of T lymphocytes known as adult T-cell leukemia (ATL) is associated with human T-cell leukemia virus type 1 (HTLV-1) infection. In this study, we show that HTLV-1-infected T cells are characterized by phosphorylation and nuclear translocation of PKC-δ. Expression of HTLV-1 regulatory protein Tax increased PKC-δ phosphorylation. Blockade of PKC-δ by rottlerin suppressed PKC-δ phosphorylation and inhibited cell viability in HTLV-1-infected T-cell lines and primary ATL cells. Rottlerin induced cell cycle arrest at the G1 phase and caspase-mediated apoptosis of HTLV-1-infected T cells. Rottlerin downregulated the expression of proteins involved in G1/S cell cycle transition, cyclin D2, CDK4 and 6, and c-Myc, resulting in dephosphorylation of retinoblastoma protein (pRb). Furthermore, rottlerin reduced the expression of important anti-apoptotic proteins (e.g., survivin, XIAP, Bcl-xL and c-FLIP) and Bcl-2 phosphorylation, and activated the pro-apoptotic protein Bax. Our results showed that permanent activation of nuclear factor-κB (NF-κB) by HTLV-1 Tax allows infected cells to escape cell cycle arrest and apoptosis and that PKC-δ mediates Tax-induced activation of NF-κB. Based on these findings, new therapies designed to target PKC-δ could be potentially useful in the treatment of ATL.

Rottlerin plays an antiviral role at early and late steps of Zika virus infection

“…We further confirmed that rottlerin inhibited the replication of ZIKV and another two enveloped viruses (VSV and HSV) in the human lung carcinoma epithelial cells A549. To date, rottlerin has been documented to inhibit the infection of many enveloped viruses, including HIV-1 ( Contreras et al., 2012 ), HTLV-1 ( Mori et al., 2015 ), Rift valley fever virus ( Filone et al., 2010 ), PRRSV ( Kang et al., 2021 ), rabies virus ( Lama et al., 2019 ), La Crosse virus ( Ojha et al., 2021a ), SARS-CoV-2 ( Chen et al., 2021 ), chikungunya virus ( Abdelnabi et al., 2017 ). This study further revealed that rottlerin conferred an antiviral activity against ZIKV and dengue virus ( Supplementary Fig.…”

“…Rottlerin, a natural polyphenol ketone compound derived from camara powder, is widely used in the function study of PKCδ because of its ability to selectively suppress PKCδ phosphorylation ( Mori et al., 2015 ). Rottlerin confers multiple physiological activities in a PKCδ-independent manner ( Maioli et al., 2012 ).…”

“…Interestingly, rottlerin confers inhibitory activity against many pathogens, including viruses, parasite ( Ietta et al., 2017 ), and bacteria ( Pandey et al., 2016 ; Shivshankar et al., 2008 ) in cultured cells and in animal models ( Kang et al., 2021 ; Ojha et al., 2021a ). The anti-pathogen effect of rottlerin is exerted either through inhibiting the activation of PKCδ, such as human immunodeficiency virus (HIV-1), human T-lymphotropic virus (HTLV-1), Rift valley fever virus (RVFV), and porcine reproductive and respiratory syndrome virus (PRRSV) ( Contreras et al., 2012 ; Filone et al., 2010 ; Kang et al., 2021 ; Mori et al., 2015 ), or through reducing the ATP levels (such as rabies virus) ( Lama et al., 2019 ). Regarding to ZIKV, a recent report showed that rottlerin inhibits its infection in human neuronal stem cells (hNSC) ( Ojha et al., 2021b ).…”

The Role of Bcl-xL Protein in Viral Infections

“…An experiment on tumor-bearing mice showed that a reduction in cancer cell viability led to the inhibition of tumor growth and promoted survival of the tested animals [108]. Mori et al [111] have determined the ability of rottlerin, a protein kinase C (PKC)-δ inhibitor, to kill HTLV-1 infected cells. The research showed that rottlerin prevented PKC-δ phosphorylation and caused several events that significantly decreased cell viability.…”

“…The research showed that rottlerin prevented PKC-δ phosphorylation and caused several events that significantly decreased cell viability. One of them was the downregulation of Bcl-xL [111]. Another study on ATLL treatment strategies was devoted to the evaluation of cerdulatinib, a chemical agent inhibiting JAK and spleen tyrosine kinase (SYK).…”