The anticancer properties and mechanism of action of tablysin-15, the RGD-containing disintegrin, in breast cancer cells

Int J Biol Macromol. 2019 May 15:129:1155-1167. doi: 10.1016/j.ijbiomac.2019.01.073. Epub 2019 Jan 17.

Abstract

αvβ3 integrin expressed on cancer cell surfaces is associated with important cancer hallmarks including survival and metastasis and is thus a potential anticancer drug target. Tablysin-15 contains the RGD motif and is a high-affinity αvβ3 integrin antagonist. The aim of this study was to investigate the antitumor effect and mechanism of action of tablysin-15 against αvβ3 integrin high-expressing breast cancer cell lines in vitro and in vivo. Tablysin-15 dose-dependently inhibited the proliferation, migration, and invasion of two breast cancer cell lines via the αvβ3 integrin in vitro. Proliferation inhibition was attributable to G0/G1 phase cell cycle arrest rather than apoptosis or necrosis. Furthermore, tablysin-15 downregulated the activity and mRNA expression of MMP-2/-9, VEGF, and COX-2 but upregulated TIMP-1/-2 mRNA in both cell lines. Further, tablysin-15 suppressed the expression of CDK2, CDK6, cyclin D1, and cyclin E, the phosphorylation of FAK, Akt, GSK-3β, and ERK, and the nuclear translocation of NF-κB while increasing the expression of the CDK inhibitor p21waf1/C1. Lastly, tablysin-15 provided effective antitumor protection in vivo. Thus, tablysin-15 inhibits the metastasis and proliferation of breast cancer cells through binding αvβ3 integrin and blocking FAK-associated signaling pathways as well as nuclear translocation of NF-κB.

Keywords: Breast cancer; Integrin; RGD; Tablysin-15; α(v)β(3).

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disintegrins / chemistry*
  • Disintegrins / pharmacology*
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Mice
  • Neoplasm Invasiveness
  • Oligopeptides / chemistry*
  • Resting Phase, Cell Cycle / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Disintegrins
  • Integrin alphaVbeta3
  • Oligopeptides
  • arginyl-glycyl-aspartic acid