Abstract
Accumulated gene mutations in cancer suggest that multi-targeted suppression of affected signaling networks is a promising strategy for cancer treatment. In the present study, we report that 7-O-succinyl macrolactin A (SMA) suppresses tumor growth by stabilizing the β-catenin destruction complex, which was achieved through inhibition of regulatory components associated with the complex. SMA significantly reduced the activities of PI3K/Akt, which corresponded with a decrease in GSK3β phosphorylation, an increase in β-catenin phosphorylation, and a reduction in nuclear β-catenin content in HT29 human colon cancer cells. At the same time, the activity of tankyrase, which inhibits the β-catenin destruction complex by destabilizing the axin level, was suppressed by SMA. Despite the low potency of SMA against tankyrase activity (IC50 of 50.1 μM and 15.5 μM for tankyrase 1 and 2, respectively) compared to XAV939 (IC50 of 11 nM for tankyrase 1), a selective and potent tankyrase inhibitor, SMA had strong inhibitory effects on β-catenin-dependent TCF/LEF1 transcriptional activity (IC50 of 39.8 nM), which were similar to that of XAV939 (IC50 of 28.1 nM). In addition to suppressing the colony forming ability of colon cancer cells in vitro, SMA significantly inhibited tumor growth in CT26 syngenic and HT29 xenograft mouse tumor models. Furthermore, treating mice with SMA in combination with 5-FU in a colon cancer xenograft model or with cisplatin in an A549 lung cancer xenograft model resulted in greater anti-tumor activity than did treatment with the drugs alone. In the xenograft tumor tissues, SMA dose-dependently inhibited nuclear β-catenin along with reductions in GSK3β phosphorylation and increases in axin levels. These results suggest that SMA is a possible candidate as an effective anti-cancer agent alone or in combination with cytotoxic chemotherapeutic drugs, such as 5-FU and cisplatin, and that the mode of action for SMA involves stabilization of the β-catenin destruction complex through inhibition of tankyrase and the PI3K/Akt signaling pathway.
Highlights
Constitutive activation of PI3K signaling is one of the most frequent gene mutations in human cancer [1,2] and results in the activation of the downstream signaling molecule Akt, which signals cell proliferation and survival
The increased activity of the β-catenin destruction complex induced by succinyl macrolactin A (SMA) was supported by an increase in axin levels as well as suppression of tankyrase activity and increased glycogen synthase kinase 3β (GSK3β) activity resulting from suppression of PI3K/Akt activity
The increased axin levels and GSK3β activity led to the phosphorylation and subsequent degradation of β-catenin in SMA-treated cancer cells (HT29) as well as tumor tissues (A549 xenograft tumor tissues)
Summary
Constitutive activation of PI3K signaling is one of the most frequent gene mutations in human cancer [1,2] and results in the activation of the downstream signaling molecule Akt, which signals cell proliferation and survival. Phosphorylation of GSK3β by PI3K/Akt in the presence of growth factors results in the inhibition of GSK3β kinase activity [9,10,11], which leads to stabilization of β-catenin. Β-catenin phosphorylation and degradation via GSK3β activation constitute one of the anti-cancer action mechanisms of PI3K/Akt inhibitors. Studies with XAV939, a selective and potent tankyrase inhibitor, have demonstrated that it stabilizes axin levels and promotes β-catenin destruction [16,17] It has been reported tankyrase 1 is overexpressed in a variety of cancers [18,19,20], and XAV939 has been shown to be an effective anti-cancer agent for CRC and other cancers [21]. The inhibition of the Wnt/β-catenin pathway by tankyrase inhibitors enhances the efficacy of EGFR inhibitor for the treatment of lung cancer [22], which suggests that tankyrase inhibitors could be used as adjuvant cancer treatments
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