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.
Highlights
Renal cell carcinoma (RCC) is a common malignancy in the World [1,2,3,4], causing a large number of cancer-associated human mortalities annually [5, 6]
The Cell Counting Kit-8 (CCK-8) optical densities (ODs) reduction was significant at 48h after GNE-477 treatment (10-100 nM), that lasted for at least 96h (Figure 1A)
Since in RCC1 cells 50 nM of GNE-477 resulted in potent cell viability reduction (Figure 1A) and colony formation inhibition (Figure 1B), this concentration was selected for further experiments
Summary
Renal cell carcinoma (RCC) is a common malignancy in the World [1,2,3,4], causing a large number of cancer-associated human mortalities annually [5, 6]. A large proportion of human RCC patients are diagnosed at late- and advanced-stages with poor prognosis [1,2,3,4]. Our previous studies have shown that melanoma antigen A6 (MAGEA6), a cancer-specific ubiquitin ligase of AMPactivated protein kinase (AMPK), is uniquely expressed in human RCC tissues and cells. MAGEA6 silencing or knockout activated AMPK signaling to inhibit mammalian target of rapamycin (mTOR) cascade, thereby inhibiting RCC cell progression [8]. A long non-coding RNA (LncRNA) THOR is expressed in RCC tissues and cells. THOR silencing resulted in potent RCC cell growth inhibition in vitro and in vivo [9]
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