Abstract
Fascaplysin, a natural product isolated from marine sponges, is a potential candidate for the development of anti-cancer drugs. However, the mechanism underlying its therapeutic effect of strengthening anti-cancer efficacy of other drugs is poorly understood. Here, we found that fascaplysin increases phosphorylation of protein kinase B (PKB), also known as AKT, and adenosine monophosphate-activated protein kinase (AMPK), which are considered therapeutic targets for cancer treatment due to their anti-apoptotic or pro-survival functions in cancer. A cell viability assay revealed that pharmacological suppression of AKT using LY294002 enhanced the anti-cancer effect of fascaplysin in various cancer cells. Similarly, fascaplysin was observed to have improved anti-cancer effects in combination with compound C, a selective AMPK inhibitor. Another challenge showed that fascaplysin increased the efficacy of methotrexate (MTX)-mediated cancer therapy by suppressing genes related to folate and purine metabolism. Overall, these results suggest that fascaplysin may be useful for improving the anti-cancer efficacy of targeted anti-cancer drugs, such as inhibitors of phosphoinositide 3-kinase AKT signaling, and chemotherapeutic agents, such as MTX.
Highlights
Chemoresistance acquired by genetic evolution during cancer treatment is closely linked to cancer recurrence and dissemination and patient death [1]
The reactivation of anti-apoptotic or pro-survival signaling during cancer treatment causes poor anti-cancer efficacy, due to chemoresistance [1]
To develop a strategy to improve the anti-cancer efficacy of fascaplysin, we investigated the activation of anti-apoptotic or pro-survival signaling upon fascaplysin treatment using a phosphorylated kinase proteome array
Summary
Chemoresistance acquired by genetic evolution during cancer treatment is closely linked to cancer recurrence and dissemination and patient death [1]. Fascaplysin is isolated from marine sponges and exerts anti-cancer effects, including the suppression of growth, angiogenesis, and metastasis in several cancer cells, through inhibition of cyclin-dependent kinase 4 (CDK4) [2,3,4,5]. We reported that fascaplysin exerts anti-cancer effects through the down-regulation of survivin and hypoxia inducible factor-1α (HIF-1α) by suppressing mechanistic target of rapamycin (mTOR)-eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)-mediated 50 -cap-dependent translation [5]. Fascaplysin exerts anti-angiogenic effects by suppressing vascular endothelial growth factor receptor 2 (VEGFR2) through non-competitive inhibition of Asp-Phe-Gly (DFG)-out [6]. Ways to improve the anti-cancer efficacy of fascaplysin for clinical application are poorly understood
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