Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties. Here, we explored its efficacy and mechanism of cell death in melanoma and acute myeloid leukemia (AML). We found that DDA induced lethal autophagy in vitro and in vivo, including primary AML patient samples, independently of melanoma Braf status or AML molecular and cytogenetic classifications. DDA is a partial agonist on liver-X-receptor (LXR) increasing Nur77, Nor1, and LC3 expression leading to autolysosome formation. Moreover, DDA inhibited the cholesterol biosynthesizing enzyme 3β-hydroxysterol-Δ8,7-isomerase (D8D7I) leading to sterol accumulation and cooperating in autophagy induction. This mechanism of death was not observed with other LXR ligands or D8D7I inhibitors establishing DDA selectivity. The potent anti-tumor activity of DDA, its original mechanism of action and its low toxicity support its clinical evaluation. More generally, this study reveals that DDA can direct control a nuclear receptor to trigger lethal autophagy in cancers.
Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autophagy is cytotoxic. DDA induces both the accumulation of pro-lysosomal sterols and stimulates the expression of regulators of autophagy such as NR4A, LC3 and TFEB through binding to the liver X receptor (LXR), a ligand-dependent transcription factor consisting of 2 isoforms, NR1H2 and NR1H3. These effects are not observed with canonical LXR agonists such as the oxysterol 22(R)-hydroxycholesterol or the synthetic molecules T0901317 and GW3965. DDA effects were measured on melanoma and acute myeloid leukemia cells including patient-derived leukemia cells in vitro and in vivo. Importantly the induction of lethal autophagy kills cells independently of their cytogenetic subgroups and does not differentiate bulk cancer cells from cancer cell progenitors. Together these data show that DDA drives LXR to induce the expression of autophagic genes leading to cancer cells death. This opens up new perspectives for cancer treatment.
Dendrogenin A (DDA) is a steroidal alkaloid that we recently discovered in mammalian tissues and normal cells. We did not detect DDA in a panel of melanoma and breast cancer cells, while DDA was present in normal Human Mammary Epithelial Cells and normal Human Epidermal Melanocytes suggesting that a deregulation of DDA metabolism may occur during carcinogenesis. We established that DDA triggered melanoma and breast cancer cells re-differentiation and death in vitro and in vivo, demonstrating its anticancer potency. In the present study, we investigated the molecular mechanisms involved in the cytotoxicity of DDA in melanoma cells. We found that DDA induced a time- and concentration-dependent cytotoxicity with the characteristics of apoptosis in human (SKMEL-28) and mouse (B16F10) melanoma cell lines. DDA induced the impairment of mitochondrial functions and activated the executioner caspase 3. However, caspase inhibitors failed to inhibit cytotoxicity suggesting that other mechanisms were involved. DDA triggered autophagy in melanoma cells and induced an autophagic flux. Genetic and pharmacological inhibition of autophagy inhibited DDA cytotoxicity showing that autophagy was involved in the cytotoxicity, which contrasts with the classical involvement of autophagy in tumor cell survival. In the search for cytotoxic effectors, we found that DDA stimulated the re-expression and re-localization of Nur77 (NR4A1) to the mitochondria, and the re-expression of Nor1 (NR4A3) in melanoma cells. We showed that pharmacological inhibition of the nucleo-cytoplasmic shuttling of Nur77, and the knock-down of Nur77 and Nor1, led to the inhibition of the cytotoxic autophagy. This establishes that Nur77 and Nor1 are involved in the induction of cytotoxic autophagy by DDA. Using a combination of molecular modeling, binding, luciferase gene reporter and transcriptional assays in tumor cells, we showed that DDA was a ligand of LXRα (NR1H3) and LXRβ (NR1H2) and a selective modulator of LXR-dependent gene expression. Interestingly, DDA displayed a specific transcriptional fingerprint compared to prototypical LXR modulators. Finally, we found that LXRβ was required for the stimulation of Nur77 and Nor1 expression by DDA and the induction of a cytotoxic autophagy. Altogether, these data established that the newly identified mammalian steroidal alkaloid DDA is a ligand of LXR that induced cytotoxic autophagy through an LXRβ-,Nur77- and Nor1-dependent mechanism in melanoma cells. Thus, DDA constitutes a promising drug candidate for melanoma treatment through an original mechanism of action. Since Nur77 and Nor1 expression has been found to be repressed in a number of aggressive tumors, DDA may represent an interesting option for the treatment of cancers expressing LXRβ. Citation Format: Gregory Segala, Mathias C. Poirot, Philippe de Medina, Michael Paillasse, Jean-Marc Lobaccaro, Sandrine Silvente-Poirot, Marc Poirot. Dendrogenin A is a newly identified mammalian steroidal alkaloid that induced autophagic cell death in melanoma cells through an LXRbeta-, Nur77- and Nor1-dependent way. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1662. doi:10.1158/1538-7445.AM2013-1662
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