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RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

Yiwu Yan, Bo Zhou, Chen Qian, Alex Vasquez, Avradip Chatterjee, Xiaopu Yuan, Edwin Posadas, Natasha Kyprianou, Beatrice S. Knudsen, Ramachandran Murali, Arkadiusz Gertych, Sungyong You, Michael R. Freeman, View ORCID ProfileWei Yang
doi: https://doi.org/10.1101/2020.05.14.096867
Yiwu Yan
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Bo Zhou
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Chen Qian
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Alex Vasquez
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Avradip Chatterjee
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Xiaopu Yuan
3Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Edwin Posadas
4Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Natasha Kyprianou
6Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
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Beatrice S. Knudsen
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
3Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Ramachandran Murali
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Arkadiusz Gertych
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
3Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Sungyong You
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Michael R. Freeman
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
7Department of Medicine, University of California Los Angeles, Los Angeles, California, United States
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Wei Yang
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
7Department of Medicine, University of California Los Angeles, Los Angeles, California, United States
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  • ORCID record for Wei Yang
  • For correspondence: wei.yang@cshs.org
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Abstract

Despite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 16, 2020.
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RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis
Yiwu Yan, Bo Zhou, Chen Qian, Alex Vasquez, Avradip Chatterjee, Xiaopu Yuan, Edwin Posadas, Natasha Kyprianou, Beatrice S. Knudsen, Ramachandran Murali, Arkadiusz Gertych, Sungyong You, Michael R. Freeman, Wei Yang
bioRxiv 2020.05.14.096867; doi: https://doi.org/10.1101/2020.05.14.096867
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RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis
Yiwu Yan, Bo Zhou, Chen Qian, Alex Vasquez, Avradip Chatterjee, Xiaopu Yuan, Edwin Posadas, Natasha Kyprianou, Beatrice S. Knudsen, Ramachandran Murali, Arkadiusz Gertych, Sungyong You, Michael R. Freeman, Wei Yang
bioRxiv 2020.05.14.096867; doi: https://doi.org/10.1101/2020.05.14.096867

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