Inhibition of aldehyde dehydrogenase 1 enhances the cytotoxic effect of retinaldehyde on A549 cancer cells.

Jin Won Park,Kyung-Han Lee,Jin Hee Lee,Seung Hwan Moon,Young Seok Cho,Kyung-Ho Jung

doi:10.18632/oncotarget.19544

Abstract

We hypothesized that aldehyde dehydrogenase1 (ALDH1) protects cancer cells from retinaldehyde-induced cytotoxicity, and that targeting this enzyme would enhance the therapeutic effect of retinaldehyde. ALDEFLUOR™ assays showed high ALDH activity in A549 and H522 cancer cells and low activity in H1666 and T47D cancer cells. Immunoblots showed that expression of ALDH1A1 and ALDH1A3 was high in A549 and H522 cells, but low in H1666 cells. HPLC confirmed that N, N-diethylaminobenzaldehyde (DEAB) inhibits ALDH-mediated disposal of retinaldehyde in A549 cells and lysates. Treatment of A549 cells with retinaldehyde in the presence of DEAB augmented reactive oxygen species production and decreased glucose uptake and oxygen consumption. Importantly, DEAB substantially potentiated the ability of retinaldehyde to dose-dependently suppress the survival of A549 and H522 cells, whereas the added effect of DEAB was minor in H1666 and T47D cells. Gene silencing with specific siRNA revealed that ALDH1A1 contributed to protection of A549 cells against retinaldehyde toxicity. These results demonstrate that ALDH1 confers protection against retinaldehyde toxicity in cancer cells.

Highlights

There is accumulating evidence that aldehyde dehydrogenase (ALDH) plays an important role in cancer [1,2,3]
We hypothesized that aldehyde dehydrogenase1 (ALDH1) protects cancer cells from retinaldehyde-induced cytotoxicity, and that targeting this enzyme would enhance the therapeutic effect of retinaldehyde
In A549 cancer cells, retinaldehyde toxicity was substantially potentiated by a specific ALDH inhibitor

Summary

Introduction

There is accumulating evidence that aldehyde dehydrogenase (ALDH) plays an important role in cancer [1,2,3]. ALDHs are a group of enzymes that catalyze the conversion of aldehydes to corresponding carboxylic acids [1]. This reaction can serve to protect cells against reactive aldehydes [4] that are potentially cytotoxic [5, 6]. ALDH1 is not merely a marker of cancer stemness, and has important roles in tumor biology [10]. Retinaldehyde is oxidized to retinoic acid by ALDH1. Previously considered active only on the retina, retinaldehyde is known to modulate the biology of a diverse range of cell types [12, 13]

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Conclusion