title: 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.
authors.affiliation: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903‑0215, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
authors.affiliation: Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa 903‑0213, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.affiliation: Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852‑8523, Japan.
authors.forename: Masachika
authors.initials: M
authors.lastname: Senba
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000328:Adult; D017209:Apoptosis; D001578:Benzopyrans / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000378:metabolism*; D015490:HTLV-I Infections / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism* / Q000821:virology*; D008301:Maleimides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D016356:Gene Products, tax; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C514970:tax protein, Human T-lymphotrophic virus 1; C085746:rottlerin; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; C088060:bisindolylmaleimide