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Depleting Tumor-NQO1 Potentiates Anoikis and Inhibits Growth of NSCLC
Brian Madajewski1, Michael A Boatman1, Gaurab Chakrabarti2
1Department of Pharmaceutical Sciences, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506.
Unlabelled:
The fundamental role that NAD(P)H/quinone oxidoreductase 1 (NQO1) plays, in normal cells, as a cytoprotective enzyme guarding against stress induced by reactive oxygen species (ROS) is well documented. However, what is not known is whether the observed overexpression of NQO1 in neoplastic cells contributes to their survival. The current study discovered that depleting NQO1 expression in A549 and H292 lung adenocarcinoma cells caused an increase in ROS formation, inhibited anchorage-independent growth, increased anoikis sensitization, and decreased three-dimensional tumor spheroid invasion. These in vivo data further implicate tumor-NQO1 expression in a protumor survival role, because its depletion suppressed cell proliferation and decreased lung tumor xenograft growth. Finally, these data reveal an exploitable link between tumor-NQO1 expression and the survival of lung tumors because NQO1 depletion significantly decreased the percentage of ALDH((high)) cancer cells within the tumor population.
Implications:
Loss of tumor-NQO1 expression inhibits tumor growth and suggests that novel therapeutics directed at tumor-NQO1 may have clinical benefit.
Insights
NAD(P)H/quinone oxidoreductase 1 (NQO1) overexpression in lung cancer cells promotes tumor survival. Depleting NQO1 inhibits cancer cell growth, invasion, and tumor xenograft development, suggesting NQO1 as a therapeutic target.
Area of Science:
- Biochemistry
- Cancer Biology
- Oncology
Background:
- NAD(P)H/quinone oxidoreductase 1 (NQO1) is a cytoprotective enzyme against reactive oxygen species (ROS) in normal cells.
- The role of NQO1 overexpression in neoplastic cell survival is not well understood.
Purpose of the Study:
- To investigate the role of NQO1 in lung adenocarcinoma cell survival and tumor growth.
- To determine if NQO1 is a viable therapeutic target for lung cancer.
Main Methods:
- NQO1 expression was depleted in A549 and H292 lung adenocarcinoma cell lines.
- Assays included ROS formation, anchorage-independent growth, anoikis sensitization, and 3D tumor spheroid invasion.
- In vivo studies involved lung tumor xenograft models.
- Flow cytometry was used to assess ALDH(high) cancer cell populations.
Main Results:
- NQO1 depletion increased ROS, inhibited anchorage-independent growth, increased anoikis sensitization, and decreased 3D tumor spheroid invasion.
- In vivo, NQO1 depletion suppressed cell proliferation and reduced lung tumor xenograft growth.
- NQO1 depletion significantly decreased the percentage of ALDH(high) cancer cells.
Conclusions:
- Tumor NQO1 expression plays a protumor survival role in lung adenocarcinoma.
- Loss of NQO1 expression inhibits tumor growth and progression.
- Targeting NQO1 may offer clinical benefits for lung cancer treatment.
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