Correction: Corrigendum: ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Wang, Junjian; Zou, June X.; Xue, Xiaochang; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C.; Louie, Maggie C.; Borowsky, Alexander D.; Gao, Allen C.; Evans, Christopher P.; Lam, Kit S.; Xu, Jianzhen; Kung, Hsing Jien; Evans, Ronald M.; Xu, Yong; Chen, Hong Wu

doi:10.1038/nm0616-692b

Cited by 8 publications

(6 citation statements)

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“…IL-23 has been reported to regulate the activation of STAT3/RORγ expression in naive CD4 T cells26–28; both STAT3 and RORγ can impact AR signaling in prostate cancer29,30. We therefore evaluated whether IL23 secreted by MDSCs impacted the STAT3/RORγ axis in prostate cancer in a non-cell autonomous manner.…”

Section: Mdscs Activate the Il23/rorγ Pathwaymentioning

confidence: 99%

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

Calcinotto

Spataro

Zagato

et al. 2018

Nature

293

303

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Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.

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Section: Mdscs Activate the Il23/rorγ Pathwaymentioning

confidence: 99%

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

Calcinotto

Spataro

Zagato

et al. 2018

Nature

293

303

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“…In castration-resistant prostate cancer (CRPC), RORγ was examined as a therapeutic target due to its overexpression and was found to directly drive androgen receptor (AR) hyperactivity through binding to an exonic RORE and partly through the NR coactivators SRC-1 and -3 ( 35 ). Therefore, inhibition of RORγ may represent a possible treatment option for CRPC.…”

Section: Cancer Relevancementioning

confidence: 99%

“…Some studies suggest that RORα is a tumor suppressor and a potential therapeutic target for BC; and based on the limited researches on RORβ in cancer, RORβ might be a tumor suppressor as well. Others have proposed that activating RORγ may exert antitumor immunity ( 34 ), while RORγ is considered as protumor candidates in prostate cancer and lung cancer ( 4 , 35 ). In this review, we summarize and discuss the structures of RORs and their roles in cancer-related processes, highlighting the potential therapeutic targets for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Retinoic Acid Receptor-Related Orphan Receptors: Critical Roles in Tumorigenesis

Fan

Yang

et al. 2018

Front. Immunol.

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Retinoic acid receptor-related orphan receptors (RORs) include RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). These receptors are reported to activate transcription through ligand-dependent interactions with co-regulators and are involved in the development of secondary lymphoid tissues, autoimmune diseases, inflammatory diseases, the circadian rhythm, and metabolism homeostasis. Researches on RORs contributing to cancer-related processes have been growing, and they provide evidence that RORs are likely to be considered as potential therapeutic targets in many cancers. RORα has been identified as a potential therapeutic target for breast cancer and has been investigated in melanoma, colorectal colon cancer, and gastric cancer. RORβ is mainly expressed in the central nervous system, but it has also been studied in pharyngeal cancer, uterine leiomyosarcoma, and colorectal cancer, in addition to neuroblastoma, and recent studies suggest that RORγ is involved in various cancers, including lymphoma, melanoma, and lung cancer. Some studies found RORγ to be upregulated in cancer tissues compared with normal tissues, while others indicated the opposite results. With respect to the mechanisms of RORs in cancer, previous studies on the regulatory mechanisms of RORs in cancer were mostly focused on immune cells and cytokines, but lately there have been investigations concentrating on RORs themselves. Thus, this review summarizes reports on the regulation of RORs in cancer and highlights potential therapeutic targets in cancer.

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“…2A ). We used XY018, a RORγ-selective antagonist [ 32 ], fatostatin (FS), which directly blocks SREBP2 by preventing its translocation to the Golgi apparatus [ 37 ] and atorvastatin (ATV), a widely used inhibitor of HMGCR to block cholesterol synthesis [ 23 ]. To define the cytotoxic profile and possible treatment side-effects, we used CD34+ cells with high levels of SREBF2 mRNA and CD34- cells with low levels as control cells.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, inhibition of retinoic acid receptor (RAR)-related orphan receptor gamma (RORγ) abolished the entire cholesterol biosynthesis program, circumventing reactivation of metabolism and the feedback loop, as previously shown in studies with triple-negative breast cancer (TNBC) and prostate cancer cells. They have demonstrated that RORγ is an important driver of tumor growth, which could be successfully diminished by newly established RORγ antagonists [ 32 , 33 ]. Importantly, RORγ has two isoforms and while RORγt (isoform 2) is highly expressed in sub-populations of immune cells and plays a critical role in the differentiation of Th17 cells, RORγ (isoform 1) has been shown to play an important role in controlling metabolic pathways [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia

Erkner,

Hentrich,

Schairer

et al. 2023

Oncogene

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Dysregulated cholesterol homeostasis promotes tumorigenesis and progression. Therefore, metabolic reprogramming constitutes a new hallmark of cancer. However, until today, only few therapeutic approaches exist to target this pathway due to the often-observed negative feedback induced by agents like statins leading to controversially increased cholesterol synthesis upon inhibition. Sterol regulatory element-binding proteins (SREBPs) are key transcription factors regulating the synthesis of cholesterol and fatty acids. Since SREBP2 is difficult to target, we performed pharmacological inhibition of retinoic acid receptor (RAR)-related orphan receptor gamma (RORγ), which acts upstream of SREBP2 and serves as master regulator of the cholesterol metabolism. This resulted in an inactivated cholesterol-related gene program with significant downregulation of cholesterol biosynthesis. Strikingly, these effects were more pronounced than the effects of fatostatin, a direct SREBP2 inhibitor. Upon RORγ inhibition, RNA sequencing showed strongly increased cholesterol efflux genes leading to leukemic cell death and cell cycle changes in a dose- and time-dependent manner. Combinatorial treatment of t(4;11) cells with the RORγ inhibitor showed additive effects with cytarabine and even strong anti-leukemia synergism with atorvastatin by circumventing the statin-induced feedback. Our results suggest a novel therapeutic strategy to inhibit tumor-specific cholesterol metabolism for the treatment of t(4;11) leukemia.

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Correction: Corrigendum: ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Cited by 8 publications

References 0 publications

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

Retinoic Acid Receptor-Related Orphan Receptors: Critical Roles in Tumorigenesis

The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia

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