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A small molecule induces integrin β4 nuclear translocation and apoptosis selectively in cancer cells with high

Shu Yan Liu1, Di Ge2,3, Li Na Chen1

  • 1Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.

Oncotarget
|February 27, 2016
PubMed

Insights

A novel small molecule, SEC, selectively induces cancer cell death in tumors with high integrin β4 (ITGB4) expression. This targeted approach involves ITGB4 nuclear translocation, activating pro-apoptosis genes for potential new cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Elevated integrin β4 (ITGB4) expression correlates with advanced carcinoma progression.
  • Targeted therapies for ITGB4-high cancer cells remain underdeveloped.

Purpose of the Study:

  • To identify and characterize a small molecule that selectively targets cancer cells with high ITGB4 expression.
  • To elucidate the molecular mechanisms underlying the selective anti-cancer effects of the identified molecule.

Main Methods:

  • Screening of small molecules for selective cytotoxicity against ITGB4-expressing cancer cells.
  • Investigating the role of ITGB4 nuclear translocation and its downstream effects.
  • Assessing the efficacy of the small molecule in an avian embryo xenograft tumor model.

Main Results:

  • A chiral small molecule, SEC, was identified that selectively induces apoptosis in cancer cells with high ITGB4 levels.
  • SEC promotes ITGB4 nuclear translocation, leading to ATF3 activation and upregulation of pro-apoptotic genes.
  • SEC enhances annexin A7 (ANXA7) binding to ITGB4, increasing ANXA7 GTPase activity and ITGB4 phosphorylation at Y1494.
  • SEC demonstrated significant inhibition of xenograft tumor growth in vivo.

Conclusions:

  • SEC represents a novel therapeutic agent with selective pro-apoptotic activity against ITGB4-high cancers.
  • The mechanism involves SEC-mediated ITGB4-ANXA7 interaction, nuclear trafficking, and subsequent activation of apoptotic pathways.
  • SEC shows promise for both in vitro and in vivo cancer treatment strategies targeting ITGB4 expression.
Keywords:
ANXA7ATF3apoptosischemical small moleculesintegrin β4 high expression cancer

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