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

作者：Mori Naoki^*; Ishikawa Chie; Senba Masachika

来源：International Journal of Oncology, 2015, 46(4): 1609-1618.

DOI：10.3892/ijo.2015.2848

• protein kinase C-delta
• adult T-cell leukemia
• human T-cell leukemia virus type 1
• Tax
• rottlerin
• nuclear factor-kappa B

Protein kinase C (PKC)-delta 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-delta. Expression of HTLV-1 regulatory protein Tax increased PKC-delta phosphorylation. Blockade of PKC-delta by rottlerin suppressed PKC-delta phosphorylation and inhibited cell viability in HTLV-1-infected T-cell lines and primary ATL cells. Rottlerin induced cell cycle arrest at the G(1) phase and caspase-mediated apoptosis of HTLV-1-infected T cells. Rottlerin downregulated the expression of proteins involved in G(1)/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-x(L) and c-FLIP) and Bcl-2 phosphorylation, and activated the pro-apoptotic protein Bax. Our results showed that permanent activation of nuclear factor-kappa B (NF-kappa B) by HTLV-1 Tax allows infected cells to escape cell cycle arrest and apoptosis and that PKC-delta mediates Tax-induced activation of NF-kappa B. Based on these findings, new therapies designed to target PKC-delta could be potentially useful in the treatment of ATL.

• 出版日期2015-4