Chronic hypoxia favours adoption to a castration-resistant cell state in prostate cancer

被引:15
|
作者
Cameron, Sarina [1 ]
Deblois, Genevieve [1 ,5 ]
Hawley, James R. [1 ,2 ]
Qamra, Aditi [1 ]
Zhou, Stanley [1 ,2 ]
Tonekaboni, Seyed Ali Madani [1 ,2 ]
Murison, Alexander [1 ]
Van Vliet, Romy [1 ]
Liu, Juan [3 ]
Locasale, Jason W. [3 ]
Lupien, Mathieu [1 ,2 ,4 ]
机构
[1] Princess Margaret Canc Res Ctr, Toronto, ON, Canada
[2] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[3] Duke Univ, Sch Med, Durham, NC USA
[4] Ontario Inst Canc Res, Toronto, ON, Canada
[5] Univ Montreal, Inst Res Immunol & Canc IRIC, Fac Pharm, Montreal, PQ H3T 1J4, Canada
关键词
BIOCHEMICAL FAILURE; ANDROGEN RECEPTOR; RADIOTHERAPY; EXPRESSION; RISK; ANGIOGENESIS; DEFINITIONS; PROGRESSION; METASTASIS; RECURRENCE;
D O I
10.1038/s41388-023-02680-z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Predicting and treating recurrence in intermediate-risk prostate cancer patients remains a challenge despite having identified genomic instability [1] and hypoxia [2, 3] as risk factors. This underlies challenges in assigning the functional impact of these risk factors to mechanisms promoting prostate cancer progression. Here we show chronic hypoxia (CH), as observed in prostate tumours [4], leads to the adoption of an androgen-independent state in prostate cancer cells. Specifically, CH results in prostate cancer cells adopting transcriptional and metabolic alterations typical of castration-resistant prostate cancer cells. These changes include the increased expression of transmembrane transporters for the methionine cycle and related pathways leading to increased abundance of metabolites and expression of enzymes related to glycolysis. Targeting of the Glucose Transporter 1 (GLUT1) identified a dependency on glycolysis in androgen-independent cells. Overall, we identified a therapeutically targetable weakness in chronic hypoxia and androgen-independent prostate cancer. These findings may offer additional strategies for treatment development against hypoxic prostate cancer.
引用
收藏
页码:1693 / 1703
页数:11
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