PI3K-Akt-mTOR inhibition by GNE-477 inhibits renal cell carcinoma cell growth in vitro and in vivo
AGING-US
Authors: Ye, Xueting; Ruanz, Jian-Wei; Huang, Hang; Huang, Wei-Ping; Zhang, Yan; Zhang, Fangyi
Abstract
Sustained activation of PI3K-Akt-mTOR cascade is important for renal cell carcinoma (RCC) cell progression. GNE-477 is a novel and efficacious PI3K-mTOR dual inhibitor. The current study tested its anti-RCC cell activity. In the primary cultured human RCC cells, GNE-477 potently inhibited cell growth, viability and proliferation, as well as cell cycle progression, migration and invasion. Furthermore, it induced robust apoptosis activation in primary RCC cells, but being non-cytotoxic to HK-2 epithelial cells and primary human renal epithelial cells. In the primary RCC cells GNE-477 inactivated PI3K-Akt-mTOR cascade by blocking phosphorylation of p85, Akt1, p70S6K1 and S6. Restoring Akt-mTOR activation by a constitutively-active Akt1 reversed GNE-477-induced anti-RCC cell activity. In nude mice intraperitoneal injection of GNE-477 potently suppressed RCC xenograft tumor growth. Collectively, targeting PI3K-Akt-mTOR cascade by GNE-477 inhibits RCC cell growth in vitro and in vivo.
SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
NATURE COMMUNICATIONS
Authors: Gassen, Nils C.; Niemeyer, Daniela; Muth, Doreen; Corman, Victor M.; Martinelli, Silvia; Gassen, Alwine; Hafner, Kathrin; Papies, Jan; Moesbauer, Kirstin; Zellner, Andreas; Zannas, Anthony S.; Herrmann, Alexander; Holsboer, Florian; Brack-Werner, Ruth; Boshart, Michael; Mueller-Myhsok, Bertram; Drosten, Christian; Mueller, Marcel A.; Rein, Theo
Abstract
Autophagy is an essential cellular process affecting virus infections and other diseases and Beclinl (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 (SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions.
COA
Publication 
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