Mori Naoki, Ishikawa Chie, Senba Masachika
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.
Int J Oncol. 2015 Apr;46(4):1609-18. doi: 10.3892/ijo.2015.2848. Epub 2015 Jan 26.
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.
蛋白激酶C（PKC）-δ是PKC家族的成员之一。它与肿瘤抑制以及多种癌症的存活有关。被称为成人T细胞白血病（ATL）的T淋巴细胞侵袭性恶性肿瘤与1型人类T细胞白血病病毒（HTLV-1）感染相关。在本研究中，我们发现HTLV-1感染的T细胞的特征在于PKC-δ的磷酸化和核转位。HTLV-1调节蛋白Tax的表达增加了PKC-δ的磷酸化。rottlerin对PKC-δ的阻断抑制了PKC-δ的磷酸化，并抑制了HTLV-1感染的T细胞系和原发性ATL细胞的细胞活力。rottlerin诱导细胞周期停滞在G1期，并介导HTLV-1感染的T细胞发生半胱天冬酶介导的凋亡。rottlerin下调了参与G1/S细胞周期转换的蛋白、细胞周期蛋白D2、细胞周期蛋白依赖性激酶4和6以及c-Myc的表达，导致视网膜母细胞瘤蛋白（pRb）去磷酸化。此外，rottlerin降低了重要的抗凋亡蛋白（如生存素、X连锁凋亡抑制蛋白、Bcl-xL和细胞凋亡抑制蛋白c-FLIP）的表达以及Bcl-2的磷酸化，并激活了促凋亡蛋白Bax。我们的结果表明，HTLV-1 Tax对核因子κB（NF-κB）的持续激活使受感染细胞能够逃避细胞周期停滞和凋亡，并且PKC-δ介导Tax诱导的NF-κB激活。基于这些发现，旨在靶向PKC-δ的新疗法可能对ATL的治疗具有潜在的应用价值。
