Shedding light on the roles of liver X receptors in cancer by using chemical probes

Abstract

Nuclear receptors, liver X receptor-α (LXRα; NR1H3) and liver X receptor-β (LXRβ; NR1H2), are considered master regulators of lipid homeostasis. During the last couple of decades, their pivotal roles in several physiological and pathological processes ranging from energy supply, immunity, cardiovascular, neurodegenerative disorders and cancer have been highlighted. In this review, the main results achieved during more recent years about our understanding of the LXR involvement in cancer has been mainly obtained using small-molecule chemical probes. Remarkably, all these probes, albeit having different structure and biological properties, have a well demonstrated anti-tumoral activity arising from LXR modulation, indicating a high potential of LXR targeting for the treatment of cancer. K E Y W O R D Scancer, chemical probes, liver X receptor, small-molecules | INTRODUCTIONThanks to their molecular characteristics, nuclear receptors have proven to be a source of very favourable druggable targets. Within the superfamily most of the members classified as classical hormone receptors have become valuable therapeutic targets, even long before their discovery. As an example, the first clinical use of cortisone dates back to 1949 (Hench, Kendall, & Slocumb, 1949), whereas the human glucocorticoid receptor (NR3C1), the first one among nuclear receptors to be cloned, was identified more than 30 years later (Hollemberg et al., 1985). This event paved the way for a decade of an intensive research in the nuclear receptor field leading to the identification of many other members of this now superfamily. However, differently from the classic endocrine nuclear receptors, these newcomers lacked endogenous ligands and therefore were referred to as orphan nuclear receptors (Mazaira et al., 2018). The de-orphanization of these orphan nuclear receptor was due to the successful discovery of their endogenous ligand(s), which allows the receptor to be regarded as "adopted."Undoubtedly, the knowledge of the natural ligand is the first step towards elucidating the physiological functions of the target protein and its potential implications in certain pathological conditions. However, without the creation of high-quality small-molecule probes, our current understanding of adopted nuclear receptors could not be what it is. Moreover, the availability of chemical probes has had a major impact on enabling and improving the drug discovery process in this area. In this context, the liver X receptors (LXRs) is a case in point.Liver X receptor-α (LXRα) and liver X receptor-β (LXRβ), which by the IUPHAR nomenclature are respectively NR1H3 and NR1H2, were discovered between 1994 and 1995 and classified as orphan receptors by different research groups

Oxysterols in cancer management: From therapy to biomarkers

“…In contrast with the previous study, in tumour-infiltrating macrophages and dendritic cells in triplenegative breast carcinoma (TNBC) patients, it was the inhibition of LXR with an inverse agonist that caused CD8 + T cell activation, tumour infiltration in vitro, and immune-dependent tumour destruction in vivo (mice) (Carpenter et al, 2019). Both these studies are further discussed in a review article also published in this issue, summarizing studies of LXRs and their chemical probes (Pontini & Marinozzi, 2020).…”

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

“…However, LXR is inhibited in tumors, which contributes to cholesterol accumulation in cancer cells. 512 , 513 Interestingly, CE levels were also significantly increased in tumors. 513 , 514 ACAT involves in synthesis of CE, which has been shown to be associated with a variety of tumors.…”

Lipid metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy

“…Abnormal activation of the cholesterol anabolic pathway is one of the signs of several tumors, which helps in the rapid growth of tumor cells to synthesize cell membranes, required lipids, and conduct necessary signals. It is characterized by the activation of cholesterol synthesis signaling SREBP-1 60 and the inhibition of cholesterol efflux signaling liver X receptors (LXRs) 61 . The activation of SREBP-1 is regulated by negative feedback of intracellular cholesterol concentration, but tumor cells can bypass this regulation in several ways, allowing continued activation.…”