Human aldehyde dehydrogenase 7A1 (ALDH7A1) expression affects cancer cell proliferation, migration and cell protection against oxidative stress


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Lina Elsalem1,Anaxagoras Fotopoulos2,Simon Allison3,Jan Moreb4,Zoe Cournia2,Klaus Pors5
1Jordan University of Science and Technology,2Biomedical Research Foundation,3University of Huddersfield,4Hematological Malignancies,5University of Bradford

Abstract

Background

ALDH7A1 has protective role against oxidative stress caused by reactive oxygen species (ROS). Abnormally high expression of ALDH7A1 was found in ovarian cancer and prostate cancer. These studies concern the ALDH7A1 expression but relatively little is known about its biological roles in cancer. Here, we report on the implication of ALDH7A1 expression in cell proliferation, migration and protection against ROS. We also report on novel chemical probes that can be used as starting points for further chemical tool discovery to study ALDH7A1 role in cancer

Method

H1299, a NSCLC cell line with low endogenous ALDH expression was stably transduced with ALDH7A1. The gene and protein expression was evaluated using qRT-PCR and western blot, respectively. ALDH activity was measured with ALDEFLUOR assay. MTT assay was used to study cell proliferation, while cell migration was measured with scratch assay. ROS generation was detected using carboxy-H2DCFDA and dsDNA breaks were measured using the expression of phosphorylated H2AX. Five compounds with the highest binding affinity for ALDH7A1 from a virtual screening of 24,000 compounds were used to probe ALDH7A1 activity

Results

ALDH7A1 enhanced H1299 cell proliferation and migration. In addition, it significantly reduced the generation of ROS (>90%). H1299/7A1 cells had significantly less phosphorylated H2AX expression (>70%). ICT11501 compound resulted in significant more ROS in H1299/7A1 cells, suggesting inhibition of ALDH7A1 functional activity.

Conclusion

Our data revealed possible role of ALDH7A1 in mediating cell proliferation and migration. To our knowledge, this is the first study describing an antioxidant role of ALDH7A1 in cancer setting and points to its role in protecting cells from DNA damage caused by ROS. ICT11501 appears as a good starting point for medicinal chemistry to be performed, leading to more potent and selective ALDH7A1 inhibitors to be developed, which can be used as tool compounds to explore the importance of ALDH7A1 in cancer