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

Mori,Naoki; Ishikawa,Chie; Senba,Masachika

doi:10.3892/ijo.2015.2848

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

Authors:
- Naoki Mori
- Chie Ishikawa
- Masachika Senba
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Affiliations: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903‑0215, Japan, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa 903‑0213, Japan, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852‑8523, Japan
Published online on: January 26, 2015 https://doi.org/10.3892/ijo.2015.2848
Pages: 1609-1618

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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.

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