The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers

Poirot, Marc; Silvente-Poirot, Sandrine

doi:10.1016/j.bcp.2018.01.046

Cited by 47 publications

(33 citation statements)

References 102 publications

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“…Within these studies, important distinctions between activation of LXRα and LXRβ need consideration. The histamine conjugated oxysterol such as dendrogenin A, preferentially activates LXRβ and drives lethal autophagy (Poirot & Silvente-Poirot, 2018) and differentiation of breast cancer cells (Bauriaud-Mallet et al, 2019), and synthetic the LXRβ agonist RGX-104 enhances cytotoxic T lymphocyte tumour destruction (Tavazoie et al, 2018). Dual LXRα/LXRβ ligands such as 26OHC convincingly slow tumour growth through the anti-proliferative activities of LXR, drive LXR dependent metastasis (Nelson et al, 2013), and substitute for estrogen to drive ER dependent breast cancer growth (Nelson et al, 2013;Wu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

Hutchinson

Websdale

Cioccoloni

et al. 2020

Preprint

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Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.

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Section: Discussionmentioning

confidence: 99%

“…Selective modulation of LXRα and LXRβ by oxysterols leads to divergent effects in cancer pathophysiology. For example, the oxysterol-histamine conjugate dendrogenin A preferentially activates LXRβ, induces lethal autophagy (Poirot & Silvente-Poirot, 2018) and differentiation of breast cancer cells (Bauriaud-Mallet et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

Hutchinson

Websdale

Cioccoloni

et al. 2020

Preprint

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“…In differentiated tissues, tumour suppressive autophagy has been observed: dendrogenin A (DDA), a newly discovered cholesterol metabolite found in mammals, possesses tumour cell differentiation and tumour suppressive properties in breast cancers, melanoma and acute myeloid leukaemia (AML), including primary AML patient samples [34, 35]. Metabolic studies demonstrated reduced DDA levels in cancer cells and human tumours compared to normal cells and tissues [35, 36]. In vitro and in vivo, DDA triggers tumour cytotoxic autophagy by binding to the liver x receptor (LXR), a nuclear receptor, and by inducing the transcriptional expression of pro-autophagic factors such as LC3b, Nur77, NOR1 and TFEB [34].…”

Section: Cytotoxic Autophagymentioning

confidence: 99%

“…Moreover, by inhibiting the D8D7I subunit of the cholesterol epoxide hydrolase enzyme (ChEH), DDA induces accumulation of sterols which contribute to increased formation of lysosomes—essential components of the autophagy machinery [34]. Thus, the nuclear receptor LXR has been identified as an essential molecular target activating lethal autophagy in cancers, and the combined action of DDA on LXR and D8D7I most likely contributes to its high efficacy by triggering sustained lethal autophagy, which is not observed with prototypical ChEH/D8D7I inhibitors or other LXR agonists [36, 37]. The anti-tumour activity and low-toxicity of DDA support the clinical development of DDA.…”

Section: Cytotoxic Autophagymentioning

confidence: 99%

Autophagy modulation: a prudent approach in cancer treatment?

Bishop

Bradshaw

2018

Cancer Chemother Pharmacol

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Autophagy is a tightly controlled process comprising lysosomal degradation and recycling of cellular proteins and organelles. In cancer, its paradoxical dual role of cytoprotection and cytotoxicity is context-dependent and controversial. Autophagy primarily acts as a mechanism of tumour suppression, by maintenance of genomic integrity and prevention of proliferation and inflammation. This, combined with immune-surveillance capabilities and autophagy's implicated role in cell death, acts to prevent tumour initiation. However, established tumours exploit autophagy to survive cellular stresses in the hostile tumour microenvironment. This can lead to therapy resistance, one of the biggest challenges facing current anti-cancer approaches. Autophagy modulation is an exciting area of clinical development, attempting to harness this fundamental process as an anti-cancer strategy. Autophagy induction could potentially prevent tumour formation and enhance anti-cancer immune responses. In addition, drug-induced autophagy could be used to kill cancer cells, particularly those in which the apoptotic machinery is defective. Conversely, autophagy inhibition may help to sensitise resistant cancer cells to conventional chemotherapies and specifically target autophagy-addicted tumours. Currently, hydroxychloroquine is in phase I and II clinical trials in combination with several standard chemotherapies, whereas direct, deliberate autophagy induction remains to be tested clinically. More comprehensive understanding of the roles of autophagy throughout different stages of carcinogenesis has potential to guide development of novel therapeutic strategies to eradicate cancer cells.

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“…The discovery of this ligand identified the existence of a new metabolic branch at the crossroad between cholesterol and histamine metabolism [42]. …”

Section: Lxrs and Their Ligands In The Ovarymentioning

confidence: 99%

Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility

Dallel

Tauveron

Brugnon

et al. 2018

IJMS

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A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women.

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The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers

Cited by 47 publications

References 102 publications

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

Autophagy modulation: a prudent approach in cancer treatment?

Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility

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