Background: Integrins are crucial anti-cancer therapy targets. We previously showed that
tablysin-15 is an integrin antagonist with its Arg-Gly-Asp motif in a novel structural context.
Objective: Here we investigated the anti-cancer effects and mechanisms of action of tablysin-15 in
Methods: Cell adhesion, competitive binding, cell viability, and ATP chemiluminescence assays
were used to analyze the binding of tablysin-15 to αvβ3 integrin and its phenotypic effects. Wound
healing, transwells, and zymography were performed to detect motility and matrix metalloproteinase-
2/-9 activities. PARP and caspase-3 cleavage were used as apoptosis assays, while LDH release
and flow cytometry were used for necrosis and cell cycle analysis. The expression of mRNAs and
proteins of target molecules was measured by qRT-PCR and western blotting, respectively.
Results: Tablysin-15 dose-dependently inhibited the proliferation, migration, and invasion of M21
cells through integrin αvβ3. The proliferation inhibition caused by tablysin-15 was attributable to
G0/G1 phase arrest rather than apoptosis or necrosis. Furthermore, tablysin-15 suppressed MMP-2/-
9 activities and the mRNA expression of MMP-2/-9 and COX-2 but was upregulated TIMP-1 in
M21 cells. Meanwhile, tablysin-15 suppressed the expression of cyclin D1/E and CDK 2/6, the
phosphorylation of FAK, Akt, and ERK, and nuclear translocation of NF-κB, while increasing the
expression of the CDK inhibitor p21waf1/C1. Taken together, tablysin-15 might inhibit melanoma cell
metastasis and proliferation by competing with αvβ3 integrin, thereby blocking FAK-associated signaling
pathways and nuclear translocation of NF-κB.
Conclusion: Tablysin-15 has reliable anti-cancer effects against M21 melanoma cells, suggesting
tablysin-15 is a promising anti-tumor drug.