Aldehyde dehydrogenase 1A1 (ALDH1A1) is a critical enzyme in the detoxification of several toxic aldehyde intermediates. ALDH1A1 expression is altered in malignant neoplasm and is associated with drug resistance, stem cell phenotype and patient survival. Since the expression pattern of ALDH1A1 in ovarian cancer was unknown, we compared ALDH1A1 in normal ovaries and, benign and malignant serous ovarian tumors to determine if expression was associated with malignant progression and stem cell markers. Furthermore, ovarian cancer cell lines were used as surrogates for ovarian cancer patients to determine if modifying ALDH1A1 expression and activity with the inhibitor diethylbenzaldehyde (DRAB), the substrate retinaldehyde (RAL), the product retinoic acid (RA) or the chemotherapeutic drug cyclophosphamide (4-HC) altered ovarian cancer cell growth and apoptosis and responses to the drug. ALDH1A1 mRNA expression and enzyme activity was dramatically decreased in malignant ovarian tumors compared to normal ovaries, whereas benign tumors were similar. ALDH1A1 expression was localized in normal ovarian stroma and surface epithelium, and some tumor cells. Expression was greater in tumors with a low grade, less aggressive phenotype. The cancer stem cell markers CD44, CD117 and CD133 were significantly increased in malignant tumors, but were not co-localized with ALDH1A1. In cell lines with inherently low and high ALDH1A1 enzyme levels, DEAB, RAL and 4-HC increased, and RA decreased, ALDH1A1 mRNA expression. RAL and RA increased growth inhibition and apoptosis in ALDH1A1low and ALDH1A1high cells; however the effect of RA was significantly higher in ALDH1A1 high than ALDH1A1low cells. Significantly greater growth inhibition and apoptosis occurred in both ALDH1A1low and ALDH1A1 high cells pre-incubated with DEAB, RAL and RA in response to 4-HC, than to 4-HC alone. These studies demonstrate for the first time that in ovarian cancer, unlike breast and lung cancers, ALDH1A1 is decreased albeit differentially, in malignant ovarian tumors and does not appear to be associated with cancer stem cell markers. ALDH1A1 appears to have an indirect role in cell growth regulation in ovarian cancer. Thus, we predict that characterizing the biologic role of ALDH1A1 activity will reveal a critical role in ovarian cancer progression and novel options for treatment
