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The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma
Shuhei Enjoji1, Ryotaro Yabe, Nobuyuki Fujiwara
1Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan.
Abstract:
Canine melanoma is one of the most important diseases in small animal medicine. Protein phosphatase 2A (PP2A), a well conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. SET/I2PP2A is an endogenous inhibitor for PP2A, which directly binds to PP2A and suppresses its phosphatase activity. Elevated SET protein levels have been reported to exacerbate human tumor progression. The role of SET in canine melanoma, however, has not been understood. Here, we investigated the potential therapeutic role for SET inhibitors in canine melanoma. The expression of SET protein was observed in 6 canine melanoma cell lines. We used CMeC-1 cells (primary origin) and CMeC-2 cells (metastatic origin) to generate cell lines stably expressing SET-targeting shRNAs. Knockdown of SET expression in CMeC-2, but not in CMeC-1, leads to decreased cell proliferation, invasion and colony formation. Phosphorylation level of p70 S6 kinase was decreased by SET knockdown in CMeC-2, suggesting the involvement of mTOR (mammalian target of rapamycin)/p70 S6 kinase signaling. The SET inhibitors, OP449 and FTY720, more effectively killed CMeC-2 than CMeC-1. We observed PP2A activation in CMeC-2 treated with OP449 and FTY720. These results demonstrated the potential therapeutic application of SET inhibitors for canine melanoma.
Insights
SET protein inhibition shows therapeutic potential for canine melanoma. Targeting SET in metastatic melanoma cells decreased proliferation and invasion, suggesting SET inhibitors could be a novel treatment strategy.
Area of Science:
- Veterinary Oncology
- Molecular Biology
- Cancer Research
Background:
- Canine melanoma is a significant disease in veterinary medicine.
- Protein phosphatase 2A (PP2A) acts as a tumor suppressor, and SET is its endogenous inhibitor.
- Elevated SET levels are linked to human tumor progression, but its role in canine melanoma is unknown.
Purpose of the Study:
- To investigate the role of SET in canine melanoma.
- To explore the therapeutic potential of SET inhibitors for canine melanoma.
Main Methods:
- Assessed SET protein expression in canine melanoma cell lines.
- Generated cell lines with stable SET knockdown using shRNAs.
- Treated cell lines with SET inhibitors (OP449 and FTY720).
- Analyzed cell proliferation, invasion, colony formation, and PP2A activity.
Main Results:
- SET protein was expressed in canine melanoma cell lines.
- SET knockdown in metastatic CMeC-2 cells reduced proliferation, invasion, and colony formation.
- SET knockdown affected mTOR/p70 S6 kinase signaling in CMeC-2 cells.
- SET inhibitors (OP449, FTY720) were more effective against CMeC-2 cells, inducing PP2A activation.
Conclusions:
- SET plays a role in canine melanoma progression, particularly in metastatic cells.
- SET inhibitors demonstrate therapeutic potential for canine melanoma by reactivating PP2A.
- Targeting SET represents a promising strategy for canine melanoma treatment.
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