Fascaplysin Exerts Anti-Cancer Effects through the Downregulation of Survivin and HIF-1α and Inhibition of VEGFR2 and TRKA

Abstract

Fascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4); however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including PD0332991 and LY2835219, on lung cancer cells that are wild-type or null for retinoblastoma (RB), indicating that unknown target molecules might be involved in the inhibition of tumor growth by fascaplysin. Fascaplysin treatment significantly decreased tumor angiogenesis and increased cleaved-caspase-3 in xenografted tumor tissues. In addition, survivin and HIF-1α were downregulated in vitro and in vivo by suppressing 4EBP1-p70S6K1 axis-mediated de novo protein synthesis. Kinase screening assays and drug-protein docking simulation studies demonstrated that fascaplysin strongly inhibited vascular endothelial growth factor receptor 2 (VEGFR2) and tropomyosin-related kinase A (TRKA) via DFG-out non-competitive inhibition. Overall, these results suggest that fascaplysin inhibits TRKA and VEGFR2 and downregulates survivin and HIF-1α, resulting in suppression of tumor growth. Fascaplysin, therefore, represents a potential therapeutic approach for the treatment of multiple types of solid cancer.

Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

“…Quantitative real-time PCR was performed as previously described [ 46 ]. Briefly, 2 μg of total RNA extracted from cultured cells by using TRIzol (Invitrogen, Waltham, MA, USA) and cDNA synthesis was performed by using a high-capacity cDNA reverse transcription kit (Applied Biosystems, Waltham, MA, USA).…”

“…As previously described [ 46 ], BALB/c-nude mice were used as human tumor xenograft models. HepG2 or SK-HEP-1 cells (1 × 10 6 ) were harvested and suspended in 100 µL of FBS-free medium.…”

“…Annexin-V staining was used to determine the proportion of apoptotic cells in accordance with a previously described experimental procedure [ 46 ]. Briefly, 1 × 10 5 cells/well were seeded onto a 6-well cell culture plate and incubated with emodin (20 μM), sorafenib (2 μM), or combination of emodin (20 μM) and sorafenib (2 μM) for 72 h. After drug treatment, the cells were collected into fresh tubes, washed with cold PBS, and centrifuged at 2000 rpm for 2 min at room temperature.…”

Anticancer Activity of Fascaplysin against Lung Cancer Cell and Small Cell Lung Cancer Circulating Tumor Cell Lines

“…The mechanisms of the antitumor effect of fascaplysin demonstrated on several carcinoma models indicate that fascaplysin is close to some drug groups such as intercalating agents, inhibitors of serine-threonine, and tyrosine kinases. Additionally, fascaplysin increases phosphorylation of AKT/PKB and adenosine monophosphate-activated protein kinase (AMPK), which feature anti-apoptotic or pro-survival functions in cancer [ 41 ]. In detail, fascaplysin abolishes the phosphorylation of mTOR, 4EBP1, and p70S6K1, which trigger the cap-dependent translation machinery and affect the expression of oncoproteins, such as survivin, c-myc, cyclin D1, VEGF, and HIF-1α.…”

Fascaplysin Sensitizes Anti-Cancer Effects of Drugs Targeting AKT and AMPK

“…Recently, we reported that fascaplysin exerts anti-cancer effects through the down-regulation of survivin and hypoxia inducible factor-1ɑ (HIF-1ɑ) by suppressing mechanistic target of rapamycin (mTOR)-eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)-mediated 5′-cap-dependent translation [ 5 ]. In addition, 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 ]. However, ways to improve the anti-cancer efficacy of fascaplysin for clinical application are poorly understood.…”