Therapeutic targeting RORγ with natural product N-hydroxyapiosporamide for small cell lung cancer by reprogramming neuroendocrine fate

Chen, Jianghe; Hu, Yiwei; Zhang, Jian; Wang, Qianyu; Wu, Xianzhong; Huang, Weiye; Wang, Qianqian; Cai, Guodi; Wang, Hong; Ou, Tian‐Miao; Feng, Weineng; Liu, Peiqing; Liu, Yonghong; Wang, Junfeng; Huang, Jie; Wang, Junjian

doi:10.1016/j.phrs.2022.106160

Cited by 12 publications

(9 citation statements)

References 42 publications

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“…RORγ was identified to play a major role in PCa due to its prominent function in activating AR gene expression and enhancing AR function in driving PCa progression [25]. Later studies by us and others showed that RORγ also plays important roles in breast cancer, pancreatic cancer and small cell lung cancer through stimulating gene programs of metabolism, cancer stemness, proliferation, EMT, drug resistance and lineage fate [26,36,37]. Like its T cell isoform RORγt, tumor cell RORγ acts primarily as a potent transcriptional activator.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Yang

Huang

et al. 2022

Cancers

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Metastatic castration-resistant prostate cancer (mCRPC) features high intratumoral cholesterol levels, due to aberrant regulation of cholesterol homeostasis. However, the underlying mechanisms are still poorly understood. The retinoid acid receptor-related orphan receptor gamma (RORγ), an attractive therapeutic target for cancer and autoimmune diseases, is strongly implicated in prostate cancer progression. We demonstrate in this study that in mCRPC cells and tumors, RORγ plays a crucial role in deregulation of cholesterol homeostasis. First, we found that RORγ activates the expression of key cholesterol biosynthesis proteins, including HMGCS1, HMGCR, and SQLE. Interestingly, we also found that RORγ inhibition induces cholesterol efflux gene program including ABCA1, ABCG1 and ApoA1. Our further studies revealed that liver X receptors (LXRα and LXRβ), the master regulators of cholesterol efflux pathway, mediate the function of RORγ in repression of cholesterol efflux. Finally, we demonstrated that RORγ antagonist in combination with statins has synergistic effect in killing mCRPC cells through blocking statin-induced feedback induction of cholesterol biosynthesis program and that the combination treatment also elicits stronger anti-tumor effects than either alone. Altogether, our work revealed that in mCRPC, RORγ contributes to aberrant cholesterol homeostasis by induction of cholesterol biosynthesis program and suppression of cholesterol efflux genes. Our findings support a therapeutic strategy of targeting RORγ alone or in combination with statin for effective treatment of mCRPC.

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Section: Discussionmentioning

confidence: 99%

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Yang

Huang

et al. 2022

Cancers

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“…To compare the anti-growth and -survival activities in cancer cells of UA and digoxin with synthetic RORγ inhibitors, we included XY018, which was characterized in its activity in antagonizing the function of RORγ in control of gene programs in the cancer cells and tumors ( Wang et al, 2016 ; Cai et al, 2019 ; Chen et al, 2022 ). In the PCa and TNBC cells, UA displayed slightly weaker but comparable inhibitory activity in modulating cell growth and survival when compared to XY018.…”

Section: Resultsmentioning

confidence: 99%

“…Although previous studies showed that UA can act as RORγt inhibitor in immune cells such as Th17 cells ( Xu et al, 2011 ; Baek et al, 2014 ), our study here provides for the first-time evidence that UA displays RORγ antagonism activity in cancer cells. Similar to UA, recent studies identified additional natural compounds such as elaiophylin ( Zheng et al, 2020 ) and N-hydroxyapiosporamide ( Chen et al, 2022 ) as RORγ antagonists. Despite their structural differences, these natural compounds share similar inhibitory effects on the gene programs controlled by RORγ in the cancer cells and tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, in search for alternative therapeutic targets for advanced cancer, RORγ in tumor cells was identified to play a critical role in tumor progression in certain types of cancer ( Zou et al, 2022a ), including castration-resistant prostate cancer (CRPC) ( Wang et al, 2016 ; Wang et al, 2020 ; Zheng et al, 2020 ; Zhang et al, 2021 ), triple-negative breast cancer (TNBC) ( Cai et al, 2019 ; Zou et al, 2022b ), small cell lung carcinoma (SCLC) ( Chen et al, 2022 ) and pancreatic ductal adenocarcinoma (PDAC) ( Lytle et al, 2019 ). In CRPC tumors and cells, RORγ directly activates androgen receptor (AR) expression and AR signaling ( Wang et al, 2016 ; Zheng et al, 2020 ; Zhang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Natural compounds ursolic acid and digoxin exhibit inhibitory activities to cancer cells in RORγ-dependent and -independent manner

2023

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Natural compounds ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have been at clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target for castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) and demonstrated that tumor cell RORγ directly activates gene programs such as androgen receptor (AR) signaling and cholesterol metabolism. Previous studies also demonstrated that UA and digoxin are potential RORγt antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function in cancer cells, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA downregulates RORγ-stimulated AR expression and AR signaling, whereas digoxin upregulates AR signaling pathway. In TNBC cells, UA but not digoxin alters RORγ-controlled gene programs of cell proliferation, apoptosis and cholesterol biosynthesis. Together, our study reveals for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in the cancer cells. Our finding that RORγ is a direct target of UA in cancer cells will help select patients with tumors that likely respond to UA treatment.

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“…NHAP was first isolated and identified as a cholesteryl ester transfer protein inhibitor from a Cytospora fungus in 1996, and its absolute configuration was determined by total synthesis of an analogue . At present, 32 related alkaloids have been reported from natural sources, mainly in the marine and plant endophytic fungi Stagonosporopsis cucurbitacearum , Pogonomyrmex badius , Arthrinium arundinis , Apiospora montagnei , Phoma sp., and Neosartorya fiscbri . − Previous studies have demonstrated that NHAP exhibits some biological activities, including antitumor activity, antifungal activities against Candida albicans or Aspergillus fumigatus , and acetylcholinesterase inhibitory activity. , However, the inhibitory effect and mechanism of NHAP on CRC cells remain unclear. Therefore, we aimed to reveal the antitumor target of NHAP and identify NHAP as a promising lead compound for CRC in the current work.…”

mentioning

confidence: 99%

The Natural Alkaloid (−)-N-Hydroxyapiosporamide Suppresses Colorectal Tumor Progression as an NF-κB Pathway Inhibitor by Targeting the TAK1–TRAF6 Complex

Shang

Wang

et al. 2023

J. Nat. Prod.

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Colorectal cancer (CRC) is an exceptionally deadly disease, whereas effective therapeutic drugs for CRC have declined over the past few decades. Natural products have become a reliable source of anticancer drugs. Previously we isolated an alkaloid named (−)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumor effects, but its effect and mechanism in CRC remain unclear. This study aimed to reveal the antitumor target of NHAP and identify NHAP as a promising lead compound for CRC. Various biochemical methods and animal models were used to investigate the antitumor effect and molecular mechanism for NHAP. These results showed that NHAP exhibited potent cytotoxicity, induced both apoptosis and autophagic cell death of CRC cells, and inhibited the NF-κB signaling pathway by blocking the interaction of the TAK1–TRAF6 complex. NHAP also markedly inhibited CRC tumor growth in vivo without obvious toxicities and possessed good pharmacokinetic characteristics. These findings identify, for the first time, that NHAP is an NF-κB inhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumor target of NHAP against CRC, which will contribute to the future development of NHAP as a novel therapeutic lead compound for CRC.

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Therapeutic targeting RORγ with natural product N-hydroxyapiosporamide for small cell lung cancer by reprogramming neuroendocrine fate

Cited by 12 publications

References 42 publications

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Natural compounds ursolic acid and digoxin exhibit inhibitory activities to cancer cells in RORγ-dependent and -independent manner

The Natural Alkaloid (−)-N-Hydroxyapiosporamide Suppresses Colorectal Tumor Progression as an NF-κB Pathway Inhibitor by Targeting the TAK1–TRAF6 Complex

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