The cholesterol-derived metabolite dendrogenin A functionally reprograms breast adenocarcinoma and undifferentiated thyroid cancer cells

Bauriaud-Mallet, Mathilde; Vija-Racaru, Lavinia; Brillouet, S.; Mallinger, Arnaud; Médina, Philippe de; Rives, Arnaud; Payré, Bruno; Poirot, Marc; Courbon, F.; Silvente-Poirot, Sandrine

doi:10.1016/j.jsbmb.2019.105390

Cited by 24 publications

(23 citation statements)

References 47 publications

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“…Focusing on the mechanism of dedifferentiation promotes a better understanding of the high invasiveness of ATCs. Many previous studies have found that some molecules and pathways, such as STRN-ALK, P53, dendrogenin A, survivin and certain long noncoding RNAs, are involved in the dedifferentiation process of thyroid cells [28][29][30][31]. Correspondingly, by analyzing the available public databases of thyroid carcinoma, we found a small signature of IRGs consisting of MMP9 and SDC2, which can predict the differentiation of thyroid carcinoma.…”

Section: Disscussionmentioning

confidence: 57%

Identification of an Immune-related Signature That Indicates the Dedifferentiation of Thyroid Cells

Wang

Qin

et al. 2020

Preprint

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Background: Patients with well-differentiated thyroid carcinoma can achieve long-term survival after reasonable treatments, but there is no standard treatment mode for poorly or undifferentiated thyroid carcinoma and its prognosis is very poor. Immune cells, especially tumor-associated macrophages, account for a large proportion of the tumor microenvironment of anaplastic thyroid carcinomas (ATCs). However, whether immune-related genes can mediate the dedifferentiation of thyroid cells is unclear.Methods: We initially compared the differences of thyroid differentiation score, infitration of immune cells and enriched pathways between ATCs and papillary thyroid carcionma (PTCs) or normal thyroid tissues in Gene Expression Omnibus database. Then, The Cancer Genome Atlas database was used to screen out the prognosis associated IRGs. A risk score was constructed and we next investigated its predictive value for differentiation by applying receiver operating characteristic (ROC) curves and correlation analyses. Kaplan-Meier curves were used to evaluated its prognostic value. We further explored the associations of the risk score with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy.Results: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower thyroid differentiation scores, higher infiltration of most immune cells and higher activation of inflammatory response. The risk score composed of MMP9 and SDC2 was significantly increased in ATCs and low differentiated PTCs. Moreover, it showed favorable predictive value for differentiation and survival. Higher risk score displayed dedifferentiation status and a worse prognosis. Additionly, the risk score was positively correlated with immune checkpoint molecules PDL1, CTLA4, IDO1, HAVCR2 and infiltration of multiple immune cells. Importantly, we found that samples with higher risk score tend to have a better response to immune checkpoint agents than lower ones.Conclusion: Our findings indicate that the risk score may not only contribute to the judgement of differentiation and prognosis of thyroid cancer, but also help to the prediction of immune cell infiltration and immune checkpoint inhibitor response.

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Section: Disscussionmentioning

confidence: 57%

Identification of an Immune-related Signature That Indicates the Dedifferentiation of Thyroid Cells

Wang

Qin

et al. 2020

Preprint

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“…Removal of TSH for 3 days reduced 131 I uptake by approximately 50%, indicating the TSH-dependent action of iodine uptake. On the other hand, Nthy-ori 3-1 cells, irrespective of the presence or absence of TSH, showed almost negligible 131 I uptake; these low levels of iodine uptake are likely nonspecific because the similarly low levels of 131 I uptake were also observed in 8505C and HepG2 cells, both of which have been shown not to express NIS [ 29 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

Reevaluation of the Effect of Iodine on Thyroid Cell Survival and Function Using PCCL3 and Nthy-ori 3-1 Cells

Kurashige

Shimamura

Nagayama

2020

Journal of the Endocrine Society

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Appropriate amount of iodine is critical for normal function of thyroid cells synthesizing thyroid hormones. Although normal thyroid cell lines such as rat PCCL3 and FRTL5 and human Nthy-ori 3-1 have been widely used for in vitro studies on physiological and pathophysiological effects of iodine on thyroid cells, we have recently pointed out the critical differences between FRTL5/PCCL3 cells and Nthy-ori 3-1 cells. Therefore, we here directly compared some of the cellular characteristics - iodine uptake, differentiated status, iodine-induced cytotoxicity and iodine-regulation of autophagy - between PCCL3 and Nthy-ori 3-1 cells. PCCL3 cells express mRNAs for TSH receptor and sodium/iodine symporter and incorporate iodine in a TSH-dependent manner, while Nthy-ori 3-1 cells do not either. Nevertheless, both cells were comparably resistant to iodine cytotoxicity: only far excess iodine (5 x 10 -2 M) killed 20 to 40% cells in 24 h with perchlorate exhibiting no effect, suggesting this cytotoxic effect is due to extracellular iodine. In contrast, a wide range of iodine (5 x 10 -9 to 5 x 10 -2 M) induced autophagy in PCCL3 cells, which was abolished by perchlorate, indicating intracellular iodine-induction of autophagy, but this effect was not observed in Nthy-ori 3-1 cells. In conclusion, it is critical to discriminate the effect of iodine incorporated into cells from that of extracellular iodine on thyroid cells. Iodine-uptake competent thyroid cells such as PCCL3 and FRTL5 cells, not Nthy-ori 3-1 cells, should be used for studies on iodine effect on thyroid cells.

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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%

“…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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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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The cholesterol-derived metabolite dendrogenin A functionally reprograms breast adenocarcinoma and undifferentiated thyroid cancer cells

Cited by 24 publications

References 47 publications

Identification of an Immune-related Signature That Indicates the Dedifferentiation of Thyroid Cells

Identification of an Immune-related Signature That Indicates the Dedifferentiation of Thyroid Cells

Reevaluation of the Effect of Iodine on Thyroid Cell Survival and Function Using PCCL3 and Nthy-ori 3-1 Cells

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

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