Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer
Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with me...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000873 |
| _version_ | 1797830057247375360 |
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| author | Wei-Yu Chen Phan Vu Thuy Dung Hsiu-Lien Yeh Wei-Hao Chen Kuo-Ching Jiang Han-Ru Li Zi-Qing Chen Michael Hsiao Jiaoti Huang Yu-Ching Wen Yen-Nien Liu |
| author_facet | Wei-Yu Chen Phan Vu Thuy Dung Hsiu-Lien Yeh Wei-Hao Chen Kuo-Ching Jiang Han-Ru Li Zi-Qing Chen Michael Hsiao Jiaoti Huang Yu-Ching Wen Yen-Nien Liu |
| author_sort | Wei-Yu Chen |
| collection | DOAJ |
| description | Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa. |
| first_indexed | 2024-04-09T13:29:59Z |
| format | Article |
| id | doaj.art-ce24179a46364bfaa956e050217da070 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-09T13:29:59Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-ce24179a46364bfaa956e050217da0702023-05-10T04:19:06ZengElsevierRedox Biology2213-23172023-06-0162102686Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancerWei-Yu Chen0Phan Vu Thuy Dung1Hsiu-Lien Yeh2Wei-Hao Chen3Kuo-Ching Jiang4Han-Ru Li5Zi-Qing Chen6Michael Hsiao7Jiaoti Huang8Yu-Ching Wen9Yen-Nien Liu10Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanDivision of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, TaiwanGenomics Research Center, Academia Sinica, Taipei, TaiwanDepartment of Pathology, Duke University Medical Center, Durham, NC, USADepartment of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan; Corresponding author. Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Corresponding author. Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.http://www.sciencedirect.com/science/article/pii/S2213231723000873Androgen deprivation therapy (ADT)Neuroendocrine prostate cancer (NEPC)Pyruvate kinase L/R (PKLR)Reactive oxygen species modulator 1 (ROMO1)MYCN proto-oncogene (MYCN) |
| spellingShingle | Wei-Yu Chen Phan Vu Thuy Dung Hsiu-Lien Yeh Wei-Hao Chen Kuo-Ching Jiang Han-Ru Li Zi-Qing Chen Michael Hsiao Jiaoti Huang Yu-Ching Wen Yen-Nien Liu Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer Redox Biology Androgen deprivation therapy (ADT) Neuroendocrine prostate cancer (NEPC) Pyruvate kinase L/R (PKLR) Reactive oxygen species modulator 1 (ROMO1) MYCN proto-oncogene (MYCN) |
| title | Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer |
| title_full | Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer |
| title_fullStr | Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer |
| title_full_unstemmed | Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer |
| title_short | Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer |
| title_sort | targeting pklr mycn romo1 signaling suppresses neuroendocrine differentiation of castration resistant prostate cancer |
| topic | Androgen deprivation therapy (ADT) Neuroendocrine prostate cancer (NEPC) Pyruvate kinase L/R (PKLR) Reactive oxygen species modulator 1 (ROMO1) MYCN proto-oncogene (MYCN) |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000873 |
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