title: The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt.
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.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Sushil C
authors.initials: SC
authors.lastname: Regmi
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Suhrid
authors.initials: S
authors.lastname: Banskota
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Sajita
authors.initials: S
authors.lastname: Shah
authors.affiliation: Research and Development Center, Daewoo Pharm. Co. Ltd, Busan, Republic of Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D060466:Axin Protein / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051820:TCF Transcription Factors / Q000378:metabolism; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C559723:7-O-succinyl macrolactin A; D000970:Antineoplastic Agents; D060466:Axin Protein; D004791:Enzyme Inhibitors; D018942:Macrolides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051820:TCF Transcription Factors; D051176:beta Catenin; D038501:Tankyrases; D051057:Proto-Oncogene Proteins c-akt