气候变化领域集成服务门户(CCPortal): A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer

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DOI	10.1073/pnas.2012748118
	A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer
	Xu L.; Yin Y.; Li Y.; Chen X.; Chang Y.; Zhang H.; Liu J.; Beasley J.; McCaw P.; Zhang H.; Young S.; Groth J.; Wang Q.; Locasale J.W.; Gao X.; Tang D.G.; Dong X.; He Y.; George D.; Hu H.; Huang J.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	GAC; Glutaminase; Prostate cancer; Therapeutic resistance
语种	英语
scopus关键词	androgen receptor; glutaminase; glutaminase C; glutamine; isoenzyme; kidney type glutaminase; telaglenastat; unclassified drug; advanced cancer; androgen deprivation therapy; animal cell; animal experiment; animal model; animal tissue; antineoplastic activity; Article; bioaccumulation; cancer hormone therapy; cancer inhibition; castration resistant prostate cancer; catabolism; cell proliferation; cell survival; cell viability; controlled study; disease exacerbation; drug efficacy; enzyme activity; enzyme inhibition; enzyme mechanism; hormone sensitivity; human; human tissue; immunohistochemistry; in vitro study; in vivo study; LNCaP cell line; male; metabolic inhibition; mouse; nonhuman; PC-3M cell line; priority journal; prostate cancer; protein expression; RNA interference; treatment failure; tumor cell; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180069
作者单位	Department of Pathology, Duke University School of Medicine, Durham, NC 27710, United States; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, United States; Duke University Health System Biochemical Genetics Laboratory, Durham, NC 27713, United States; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, United States; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, United States; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States; Department of Urologic Science, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, United States; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, United States; School of Medicine, Southern University of Science and Technology, Shenzhen,...
推荐引用方式 GB/T 7714	Xu L.,Yin Y.,Li Y.,et al. A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer[J],2021,118(13).
APA	Xu L..,Yin Y..,Li Y..,Chen X..,Chang Y..,...&Huang J..(2021).A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Xu L.,et al."A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).