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Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis.
Yan, Yiwu; Zhou, Bo; Qian, Chen; Vasquez, Alex; Kamra, Mohini; Chatterjee, Avradip; Lee, Yeon-Joo; Yuan, Xiaopu; Ellis, Leigh; Di Vizio, Dolores; Posadas, Edwin M; Kyprianou, Natasha; Knudsen, Beatrice S; Shah, Kavita; Murali, Ramachandran; Gertych, Arkadiusz; You, Sungyong; Freeman, Michael R; Yang, Wei.
Affiliation
  • Yan Y; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Zhou B; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Qian C; InterVenn Biosciences, South San Francisco, CA, USA.
  • Vasquez A; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Kamra M; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Chatterjee A; Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
  • Lee YJ; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Yuan X; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Ellis L; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Di Vizio D; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Posadas EM; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Kyprianou N; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Knudsen BS; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Shah K; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Murali R; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Gertych A; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • You S; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Freeman MR; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA.
  • Yang W; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Nat Commun ; 13(1): 669, 2022 02 03.
Article in En | MEDLINE | ID: mdl-35115556
Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Gene Expression Regulation, Neoplastic / Proto-Oncogene Proteins c-myc / Receptor-Interacting Protein Serine-Threonine Kinase 2 Limits: Animals / Humans / Male Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Gene Expression Regulation, Neoplastic / Proto-Oncogene Proteins c-myc / Receptor-Interacting Protein Serine-Threonine Kinase 2 Limits: Animals / Humans / Male Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: Country of publication: