Abstract A64: NQO1 depletion in non-small lung cancer cells decreases their tumorigenicity by reducing the ALDH (high) cancer stem cell population

Abstract

Abstract Lung cancer is the leading cause of cancer related deaths in the world. In 2015, roughly 160,000 people in the U.S. alone will succumb to the disease. The high mortality is mainly due to late diagnosis and therapeutic resistance, followed by disease progression. One mechanism by which lung cancer is able to circumvent treatment is through the existence of cancer stem cells (CSCs). CSCs are a subpopulation of cells within the heterogenous tumor that are capable of self-renewal, are less sensitive to therapeutics and are believed to be responsible for disease progression, metastasis, and relapse. Aldehyde dehydrogenase (ALDH) high activity has been linked to the cancer stem cell phenotype in various cancers; and the elimination of cells within the heterogenous tumor that have ALDH (high) activity has been associated with decreased tumorigenicity. NADPH quinone oxidoreductase-1 (NQO1) is a two-electron oxidoreductase that is highly overexpressed in many cancers including non-small cell lung cancer. In normal cells NQO1 is expressed only at low levels, but plays a significant role in regulating oxidative stress. Thus, we hypothesized that the noted overexpression of NQO1 in most cancers may be due to its critical role in tumor survival. Specifically, in balancing the noted elevated levels of oxidative stress observed in cancer cells. Thus, reducing NQO1 expression in tumor cells may tip the balance towards pro-death instead of pro-survival. In our studies we used two different shRNA constructs to deplete NQO1 expression and assayed the ability of the knockdown cells to perform in assays that define a tumors ability to participate in disease progression. In brief, our data showed that NQO1 depleted non-small cell lung cancer cell lines had decreased colony formation in soft agar assays, increased detachment induced cell death (anoikis), increased oxidative stress and increased apoptosis. In addition, shNQO1 knockdown caused a depletion in ALDH (high) activity, suggesting that the cancer stem cell population was reduced due to the loss of NQO1 expression. Our in vivo data supported our in vitro data since athymic mice bearing shQNO1 tumors had significantly longer long-term survival and less tumor growth as compared to mice bearing vector-control tumors. In conclusion, our data strongly suggest that NQO1 depletion is a viable target for lung cancer stem cell reduction. Furthermore, our data suggest that implementation of NQO1-directed therapies to reduce cancer stem cells will lead to improved survival in patients whose tumors overexpress NQO1. Citation Format: Brian Madajewski, Michael A. Boatman, Erik A. Bey. NQO1 depletion in non-small lung cancer cells decreases their tumorigenicity by reducing the ALDH (high) cancer stem cell population. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A64.