Retinoids: Molecular Aspects and Treatment in Premalignant Lesions and Cervical Cancer

Abstract

Persistent infection with high-risk human papillomavirus remains the primary factor associated with the progression of cervical squamous intraepithelial lesions and the development of cervical cancer. Nevertheless, a combination of factors, including genetic predisposition, immune response, hormonal influences, and nutritional status, contribute synergistically to the development of cervical cancer. Among the various factors involved in the pathogenesis and therapy of cervical cancer, retinoids have gained considerable attention due to their multifaceted roles in different cellular processes. This review investigates defects within the vitamin A metabolism pathway and their correlation with cervical cancer. Additionally, it integrates epidemiological and experimental findings to discuss the potential utility of retinoid-based therapies, either alone or combined with other therapies, as agents against premalignant lesions and cervical cancer.

Keywords: ATRA; Vitamin A; cervical cancer; human papillomaviruses; retinoids.

Figure 1.

Vitamin A metabolism pathway. Carotenoids and retinyl esters are acquired through dietary intake. (1) Digestive enzymatic action can convert retinyl esters into retinol and free fatty acids within the small intestine. After that, the carotenes and retinol form micelles, facilitating their absorption via transporters such as SRB1, CD36, or STRA6. Once inside enterocytes, carotenes undergo cleavage by BCO1, resulting in the formation of retinal, which is subsequently converted into retinol by RDH. Retinol then binds to CRBP2; LRAT esterifies retinol to form retinyl esters. Then, retinyl esters, retinal, and carotenes are transported as chylomicrons to the liver via the lymphatic system. (2) In the liver, REHs convert retinyl esters into retinol, which binds to RBP4. Excess retinyl esters may be stored in hepatic stellate cells. Retinol or retinyl esters bind to RBP4 within a complex with TTR for transport from the liver, forming retinol-RBP4-TTR. (3) This complex enters circulation until reaching target cells, where STRA6 binds to facilitate retinol entry. Retinol binds to CRBP1 within the target cell and is metabolized to retinal by RDH. Subsequently, the retinal is oxidized to ATRA by ALDH. ATRA can bind to CRABP2 or FABP5 and translocate into the nucleus to interact with nuclear receptors, including RAR/RXR and PPAR/RXR.^, SRB1: Scavenger receptor class B member 1, CD36: cluster of differentiation 36, STRA6: Receptor for retinol uptake STRA6, BCO1: Beta,beta-carotene 15,15′-dioxygenase, RDH: Retinol dehydrogenase, CRBP2: Cellular retinol-binding protein II, LRAT: Lecithin retinol acyltransferase, REH: Retinyl ester hydrolases, RBP4: Retinol-binding protein 4, TTR: Transthyretin, ATRA: all trans retinoic acid, ALDH: Aldehyde dehydrogenases, CRABP2: Cellular retinoic acid-binding protein 2, FABP5: Fatty acid-binding protein 5,: RAR: Retinoic acid receptor, RXR: Retinoic X receptor, PPAR: Peroxisome proliferator-activated receptor. All genes, protein, and symbols were written according to HUGO Gene Nomenclature Committee (HGNC, https://genenames.org/) and UniProt (https://www.uniprot.org/).