Aldehyde dehydrogenases and cancer stem cells

Highlights

• Aldehyde dehydrogenase (ALDH) is cancer prognostic marker and plays as marker of cancer stem cells (CSCs).

• ALDH takes part in retinoic acid-mediated signalling, reducing active oxygen species and resisting drug toxicity.

• ALDH is regulated by RA, Notch, Wnt or TGF-β pathways in CSCs.

Abstract

Aldehyde dehydrogenases (ALDHs), as essential regulators of aldehyde metabolism in the human body, protect organisms from damage induced by active aldehydes. Given their roles in different cancer types, ALDHs have been evaluated as potential prognostic markers of cancer. ALDHs exhibit high activity in cancer stem cells (CSCs) and may serve as markers of CSCs. Moreover, studies indicated that ALDHs and their regulated retinoic acid, reactive oxygen species and reactive aldehydes metabolism were strongly related with various properties of CSCs. Besides, recent research evidences have demonstrated the transcriptional and post-translational regulation of ALDH expression and activation in CSCs. Thus, this review focuses on the function and regulation of ALDHs in CSCs, particularly ALDH1A1 and ALDH1A3.

Introduction

Aldehyde dehydrogenases (ALDHs), broadly defined as a superfamily of NADP(+)-dependent enzymes, participate in aldehyde metabolism, catalysing the oxidation of exogenous aldehydes (drugs and ethanol) and endogenous aldehydes (lipid, amino acids, or vitamins) into their corresponding carboxylic acids [1]. The primary toxicity of aldehydes can induce enzyme inactivation, DNA damage, impaired cellular homeostasis and even cell death by forming adducts with various cellular targets including glutathione, nucleic acids and amino acids [2], [3]. Deficiency and polymorphisms of ALDHs in organisms are related to diseases such as Parkinson's disease, Type II hyperprolinaemia, hypertension and Sjögren–Larsson syndrome, and may even contribute to the occurrence of carcinoma [4], [5], [6], [7], [8]. Numerous studies have indicated that tumours with high malignancy have high levels of ALDHs [9], [10].

Cancer stem cells (CSCs) may have been first identified in teratocarcinomas [11], [12], with its initial clues date back to the 19th century [13]. Kleinsmith and Pierce [12] established the immortal pluripotent teratocarcinoma lines from a single transplanted multi-potent malignant cell, strongly suggesting the existence of CSCs. Further data demonstrated the existence of CSCs in leukaemia and multiple solid tumours [14], [15], [16]. CSCs, also called tumour-initiating cells, comprise a small distinct subpopulation of tumour cells which possess high self-renewal properties, multiple differentiation capacity, tumourigenesis and drug resistance. The theory of cancer stem cell proposes an attractive cellular mechanism for the current unsatisfactory treatments. However, since the first discovery, challenges have arisen on how to effectively target CSCs. Recent studies have exhibited the importance of metabolic reprogramming as the hallmark of cancer and a growing number of results have established a link between material metabolisms and CSCs. For instance, the metabolic enzyme glycine decarboxylase, which functions in glycine metabolism, drive the tumorigenicity of CSCs in non-small cell lung cancer (NSCLC) [17]. Mutations in metabolic enzymes such as isocitrate dehydrogenase-2 play multiple roles in leukaemia initiation and maintenance [18]. As important metabolic enzymes in CSCs, ALDHs and their metabolic substrates retinoic acid (RA), reactive oxygen species (ROS) and reactive aldehydes directly and indirectly influence the various cellular processes in CSCs; these processes include target gene expression, protein translation and signal transduction. Moreover, ALDHs are being widely used to isolate and identify various CSCs and are regarded as consistent CSC markers [19], compared with other CSC surface markers, such as CD24, CD44, CD133, CD166 and epithelial cell adhesion molecule, which are limited to specific types of tumours [20], [21].

ALDHs have vital roles as metabolic enzymes and universal markers in CSCs. Accumulating evidence on the functional role of ALDHs in CSCs is available; however, the specific mechanisms involved in the regulation of ALDHs in CSCs remain unclear. Thus, this review focuses on the biological effects of ALDHs and the mechanisms underlying ALDH regulation in CSCs and provides insights into the potential therapeutic applications of ALDHs in CSC elimination.