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The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt.

Regmi SC, Park SY, Kim SJ, Banskota S, Shah S, Kim DH, Kim JA - PLoS ONE (2015)

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Anti-tumor effect of SMA alone and in combination with cisplatin in the A549 human non-small cell lung cancer xenograft model.(A) Tumor-bearing BALB/c nude mice were treated intraperitoneally with SMA, cisplatin, or both, for 7 consecutive days following a 3-day intermission as one cycle. Six mice per group were used. (B) Tumor growth was monitored by measuring tumor size. (C) Twenty eight days after commencing three cycles of treatment, tumor tissues were isolated and the tumor weights were measured. (D-F) Western blotting of tumor tissues on signaling molecule activation (D), nuclear localization of β-catenin (E), and protein expression of target genes (F). C and N in (E) represent cytosol and nucleus, respectively. *P<0.05 vs. vehicle-treated controls. #P<0.05 vs. cisplatin alone-treated animals. $P<0.05 vs. SMA alone-treated animals.
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pone.0141753.g005: Anti-tumor effect of SMA alone and in combination with cisplatin in the A549 human non-small cell lung cancer xenograft model.(A) Tumor-bearing BALB/c nude mice were treated intraperitoneally with SMA, cisplatin, or both, for 7 consecutive days following a 3-day intermission as one cycle. Six mice per group were used. (B) Tumor growth was monitored by measuring tumor size. (C) Twenty eight days after commencing three cycles of treatment, tumor tissues were isolated and the tumor weights were measured. (D-F) Western blotting of tumor tissues on signaling molecule activation (D), nuclear localization of β-catenin (E), and protein expression of target genes (F). C and N in (E) represent cytosol and nucleus, respectively. *P<0.05 vs. vehicle-treated controls. #P<0.05 vs. cisplatin alone-treated animals. $P<0.05 vs. SMA alone-treated animals.

Mentions: Next, we examined whether SMA could exert anti-proliferative activity in A549 human non-small cell lung cancer cells (NSCLC), which possess mutant APC and wild type β-catenin similar to HT29 colon cancer cells. Treatment with SMA inhibited A549 human lung cancer cell proliferation (Fig 1), and the IC50 value of SMA against serum- or GSK3β inhibitor-induced cancer cell proliferation was the lowest in A549 cells (Table 1). The anti-tumor effect and action mechanism of SMA were further examined in a mouse tumor model with a xenograft of A549 cells (drug treatment scheme is shown in Fig 5A). As shown in Fig 5B, SMA significantly suppressed tumor growth in this model. Because cisplatin is often the first treatment option for monotherapy or for combination chemotherapy in patients with advanced NSCLC, we also compared the effect of SMA with cisplatin. In the A549 xenograft model, 50 mg/kg SMA had an anti-tumor effect similar to 1 mg/kg cisplatin. Furthermore, combined therapy with cisplatin (1 mg/kg) and SMA (50 mg/kg) had a much stronger anti-tumor effect than cisplatin or SMA alone (Fig 5B and 5C). Western blot analyses of tumor tissues showed SMA significantly suppressed the phosphorylation of PI3K (p85), Akt, and GSK3β (Fig 5D). In contrast, axin levels were increased by SMA. Cisplatin treatment induced a similar but less potent effect on the phosphorylation of the signaling proteins. SMA in a combination regimen with cisplatin induced strong inhibitory effects on the signaling molecules. Nuclear β-catenin levels in tumor tissues were not inhibited by cisplatin alone, but were dramatically suppressed by SMA and synergistically by SMA plus cisplatin (Fig 5E). Regarding c-Myc and cyclin D1 levels, although cisplatin suppressed their nuclear levels, treatment with SMA plus cisplatin had a much stronger effect (Fig 5F).


The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt.

Regmi SC, Park SY, Kim SJ, Banskota S, Shah S, Kim DH, Kim JA - PLoS ONE (2015)

Anti-tumor effect of SMA alone and in combination with cisplatin in the A549 human non-small cell lung cancer xenograft model.(A) Tumor-bearing BALB/c nude mice were treated intraperitoneally with SMA, cisplatin, or both, for 7 consecutive days following a 3-day intermission as one cycle. Six mice per group were used. (B) Tumor growth was monitored by measuring tumor size. (C) Twenty eight days after commencing three cycles of treatment, tumor tissues were isolated and the tumor weights were measured. (D-F) Western blotting of tumor tissues on signaling molecule activation (D), nuclear localization of β-catenin (E), and protein expression of target genes (F). C and N in (E) represent cytosol and nucleus, respectively. *P<0.05 vs. vehicle-treated controls. #P<0.05 vs. cisplatin alone-treated animals. $P<0.05 vs. SMA alone-treated animals.
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pone.0141753.g005: Anti-tumor effect of SMA alone and in combination with cisplatin in the A549 human non-small cell lung cancer xenograft model.(A) Tumor-bearing BALB/c nude mice were treated intraperitoneally with SMA, cisplatin, or both, for 7 consecutive days following a 3-day intermission as one cycle. Six mice per group were used. (B) Tumor growth was monitored by measuring tumor size. (C) Twenty eight days after commencing three cycles of treatment, tumor tissues were isolated and the tumor weights were measured. (D-F) Western blotting of tumor tissues on signaling molecule activation (D), nuclear localization of β-catenin (E), and protein expression of target genes (F). C and N in (E) represent cytosol and nucleus, respectively. *P<0.05 vs. vehicle-treated controls. #P<0.05 vs. cisplatin alone-treated animals. $P<0.05 vs. SMA alone-treated animals.
Mentions: Next, we examined whether SMA could exert anti-proliferative activity in A549 human non-small cell lung cancer cells (NSCLC), which possess mutant APC and wild type β-catenin similar to HT29 colon cancer cells. Treatment with SMA inhibited A549 human lung cancer cell proliferation (Fig 1), and the IC50 value of SMA against serum- or GSK3β inhibitor-induced cancer cell proliferation was the lowest in A549 cells (Table 1). The anti-tumor effect and action mechanism of SMA were further examined in a mouse tumor model with a xenograft of A549 cells (drug treatment scheme is shown in Fig 5A). As shown in Fig 5B, SMA significantly suppressed tumor growth in this model. Because cisplatin is often the first treatment option for monotherapy or for combination chemotherapy in patients with advanced NSCLC, we also compared the effect of SMA with cisplatin. In the A549 xenograft model, 50 mg/kg SMA had an anti-tumor effect similar to 1 mg/kg cisplatin. Furthermore, combined therapy with cisplatin (1 mg/kg) and SMA (50 mg/kg) had a much stronger anti-tumor effect than cisplatin or SMA alone (Fig 5B and 5C). Western blot analyses of tumor tissues showed SMA significantly suppressed the phosphorylation of PI3K (p85), Akt, and GSK3β (Fig 5D). In contrast, axin levels were increased by SMA. Cisplatin treatment induced a similar but less potent effect on the phosphorylation of the signaling proteins. SMA in a combination regimen with cisplatin induced strong inhibitory effects on the signaling molecules. Nuclear β-catenin levels in tumor tissues were not inhibited by cisplatin alone, but were dramatically suppressed by SMA and synergistically by SMA plus cisplatin (Fig 5E). Regarding c-Myc and cyclin D1 levels, although cisplatin suppressed their nuclear levels, treatment with SMA plus cisplatin had a much stronger effect (Fig 5F).

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus