Abstract
In the current study, we showed that the combination of mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not apoptotic cell death was important for the cytotoxic effects by the co-administration. We observed that the combination of RAD001 and MK-2206 exerted enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in HGC-27 cells. In conclusion, these results suggested that the synergistic anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent autophagic cell death pathway.
Highlights
Extensive translational research and development of experimental therapeutics on gastric cancers have been achieved recently, there has been no significant improvement in overall survival for gastric cancer patients [1,2,3]
One important pathway that is frequently dysregulated is phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB or Akt)/mammalian target of rapamycin signaling cascade [4,5], which is activated by various growth factor receptors (i.e. HER2(human epidermal growth factor receptor-2) [6]) or by phosphatase and tensin homolog (PTEN) mutation [7]
Our results showed that the combination of RAD001 and MK-2206 exerted synergistic anti-cancer activity against PTEN mutant gastric cancer cell lines, and suggested that ERK mitogenactivated protein kinases (MAPK)-dependent autophagy pathway, but not apoptosis mediated this process
Summary
Extensive translational research and development of experimental therapeutics on gastric cancers have been achieved recently, there has been no significant improvement in overall survival for gastric cancer patients [1,2,3]. One key hurdle is the molecular heterogeneity of gastric cancers, which impedes uniform application of specific molecularly targeted agents [1,2,3]. One important pathway that is frequently dysregulated is phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB or Akt)/mammalian target of rapamycin (mTOR) signaling cascade [4,5], which is activated by various growth factor receptors (i.e. HER2(human epidermal growth factor receptor-2) [6]) or by phosphatase and tensin homolog (PTEN) mutation [7]. Dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of anti-neoplastic agents [11]. Various inhibitors designed to target this pathway are being developed for clinical use [4,8,12], and the combination of these inhibitors with chemotherapy has successfully attenuated chemotherapeutic resistance in gastric cancer cell lines [4]
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