Dataset Information

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

ABSTRACT: In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse phase

SUBMITTER: tianxiao li

PROVIDER: MTBLS8034 | MetaboLights | 2023-10-11

REPOSITORIES: MetaboLights

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Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer.

Li Xiao X Li Fei F Ye Fei F Guo Haotian H Chen Wentao W Jin Jia J Wang Yiran Y Dai Pengfei P Shi Huili H Tao Hongru H Dang Wenzhen W Ding Yiluan Y Wang Mingchen M Jiang Hualiang H Chen Kaixian K Zhang Naixia N Gao Dong D Zhang Yuanyuan Y Luo Cheng C

Cell reports 20230714 7

In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directl ...[more]

PMID: 37453063

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Project description:Prostate cancer is the commonest male cancer in Europe and the USA. The androgen receptor is a key transcription factor contributing to the development of all stages of the disease. In addition, other transcription factors have been associated with poor prognosis in prostate cancer, amongst which c-Myc is a well-established oncogene in many other cancers. We have previously reported that a role for the androgen receptor in prostate cancer is to promote glycolysis and anabolic metabolism. Many of these metabolic pathways are also c-Myc-regulated in other cancers. In this study we report that de novo purine biosynthesis is a c-Myc-dependent pathway in prostate cancer cells as determined by commensurate changes in the levels of enzymes in the pathway in response to siRNA knockdown of c-Myc and inducible overexpression of c-Myc. In addition c-Myc is recruited to the promoters of genes in the pathway as determined by chromatin immunoprecipitation. Using immunohistochemistry and real-time transcript detection we show that two enzymes (PAICS and IMPDH2) within the pathway are overexpressed in prostate cancers. An inhibitor of IMPDH2 reduces cell proliferation and significantly reduces the levels of guanosine triphosphate within treated cells. This imposes nucleolar stress on cells as determined by significant reductions in the levels of guanine nucleotide binding protein-like 3 (GNL3). In addition the levels of c-Myc, p53 and the androgen receptor are affected and the expression of tumour suppressive microRNA-34b is increased. Combining the IMPDH2 inhibitor with anti-androgens results in a combinatorial inhibition of cell proliferation. In conclusion we propose using enzymes within the de novo purine biosynthesis as cancer biomarkers and applying drugs to alter the flux through this pathway may represent an effective means of stratifying patients for therapy and sensitising some to AR-targeted therapies. Total RNA of three biological replicates for each condition was extracted using the RNeasy kit (Qiagen), conditions are: 5 h vehicle, 5 h Doxycycline, 12 h vehicle, 12 h Doxycyline

Dataset Information

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Publications

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer.

Similar Datasets

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