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Targeting of Lung Cancer Stem Cell Self-Renewal Pathway by a Small Molecule Verrucarin J

  • Karen Udoh
  • Seema Parte
  • Kelsey Carter
  • Aaron Mack
  • Sham S. KakarEmail author
Article
  • 204 Downloads

Abstract

Despite considerable advances made in understanding of lung cancer biology, there has been meek improvement in lung cancer treatment outcome with 4% to 5% increase in 5-year survival rates in the last four decades. Underlying problem of lung cancer recurrence and poor prognosis is attributed to the presence of cancer stem cells (CSCs) which possess the potential to differentiate, proliferate and trigger chemo-resistance, tumor progression and metastasis, despite initial elimination of the tumor. To address specific targeting of CSCs, we investigated the effects of a small molecule Verrucarin J (VJ) on lung cancer cell lines A549 and H1793. VJ significantly inhibited cell proliferation of both cell lines, with IC50 values of approximately 10 nM for A549 and 20 nM for H1793 respectively after 48 h of treatment. A549 cell line when treated with VJ, induced cell apoptosis with concomitant down regulation of key CSC specific genes- ALDH1, LGR5, OCT4 and CD133 in a dose-dependent manner. To delineate the molecular mechanism by which VJ targets lung cancer cells and CSCs, we determined the effects of VJ on CSC self-renewal pathways Wnt1/β-catenin and Notch1. Treatment of A549 cell line with VJ inhibited significantly both the signalling pathways, suggesting inhibition of expression of CSC genes by VJ through the inhibition of CSC self-renewal signalling pathways. Taken together, our results suggest that VJ may serve as a potent anticancer drug to target cancer cells and CSCs.

Keywords

Lung cancer Lung cancer stem cells Verrucarin J Cancer stem cell self-renewal Anti-cancer drug 

Notes

Funding

This study was funded by a grant from NIH/NCI UO1CA2177798 (subcontract, SSK).

Compliance with Ethical Standards

Competing Interests

The Authors declare that they have no competing interest.

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Authors and Affiliations

  1. 1.Department of PhysiologyUniversity of LouisvilleLouisvilleUSA
  2. 2.James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA

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