Date on Senior Honors Thesis

5-2018

Document Type

Senior Honors Thesis

Degree Name

B.S.

Department

Biology

Author's Keywords

lung cancer; cancer stem cells; Verrucarin J; WNT; ALDH1

Abstract

Lung cancer is the leading cause of cancer mortality in the United States. The development of drug resistance with cisplatin or platinum/taxane combination chemotherapies has led patients to suffer from recurrent lung cancer. These chemotherapy treatments target cancer cells but leave behind cancer stem cells (CSCs). CSCs are stem-like tumor cells that have the potential to differentiate and proliferate. This allows the cancer to relapse even after initial elimination of the tumor. Investigations were performed on a secondary metabolite from the Myrothecium fungus family called Verrucarin J (VJ) to see its effects in lung cancer cell lines. VJ significantly inhibits cell proliferation in lung cancer cell lines A549 and H1793. The IC50 of VJ was approximately 10 nM in A549 after 48 h of treatment and 20 nM in H1793 after 72 h of treatment. Treatment of the A549 cell line with VJ induced apoptosis and reduced expression levels of key markers and genes found in cancer stem cells, such as ALDH1, Notch1, HEY1, CD 133, Oct 4, β-catenin, WNT1, TCF-4, and LGR5, in a dose-dependent manner. The mechanism that VJ targets the lung cancer cells and CSCs is currently being investigated by considering the WNT canonical signaling pathway. Treatment of the GSK-3 inhibitor (CHIR99021) in A549 cell lines increased expression levels of specific canonical WNT signaling pathway genes including β-catenin, Cyclin D1, LGR5, c-Myc and TCF-4. Preliminary results of the combination treatment of VJ and GSK-3 inhibitor in A549 cell line indicate that VJ potentially targets the WNT canonical signaling pathway. However, further experiments are needed to confirm where exactly VJ is targeting that pathway. From these experiments, Verrucarin J has the potential application to be a novel chemotherapeutic drug.

Lay Summary

Verrucarin J inhibits the cell proliferation of both A549 cells and H1793 cells in a dose and time-dependent manner, and induces apoptosis. Key stem cell markers were detected using Real -Time PCR and levels of their expression were inhibited by Verrucarin J in a dose-dependent manner. The use of the GSK-3 inhibitor increased the levels of WNT signal transduction genes such as β-catenin, TCF-4, LGR5, Cyclin D1, and c-Myc. The results of this project suggest that Verrucarin J is an effective drug for targeting lung cancer cells as well as cancer stem cells.

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