TY - JOUR
T1 - Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
AU - Yan, Yiwu
AU - Zhou, Bo
AU - Qian, Chen
AU - Vasquez, Alex
AU - Kamra, Mohini
AU - Chatterjee, Avradip
AU - Lee, Yeon Joo
AU - Yuan, Xiaopu
AU - Ellis, Leigh
AU - Di Vizio, Dolores
AU - Posadas, Edwin M.
AU - Kyprianou, Natasha
AU - Knudsen, Beatrice S.
AU - Shah, Kavita
AU - Murali, Ramachandran
AU - Gertych, Arkadiusz
AU - You, Sungyong
AU - Freeman, Michael R.
AU - Yang, Wei
N1 - Funding Information:
We thank Drs. Jayoung Kim, Gina (Chia-Yi) Chu, Stephen Freedland, Hisashi Tanaka, and their group members, other members of the Freeman and Di Vizio labs, and Dr. Yanping Wang for helpful suggestions. We are grateful to Drs. Mandana Zandian and Jasmine Wang for lab assistance, as well as the Biobank and Translational Research Shared Resource of Cedars-Sinai Cancer. Cartoons in Figs. g and were created with BioRender.com. This work was supported by NCI R01 awards 1R01CA218526 and 1R01CA232574, Cedars-Sinai Development of Prostate Cancer Fund, Cedars-Sinai Precision Health Award, and UCLA CTSI Core Voucher Award [W.Y.] and the Department of Defense (DoD)—Early Investigator Research Award W81XWH-18-1-0476 [Y.Y.].
Funding Information:
We thank Drs. Jayoung Kim, Gina (Chia-Yi) Chu, Stephen Freedland, Hisashi Tanaka, and their group members, other members of the Freeman and Di Vizio labs, and Dr. Yanping Wang for helpful suggestions. We are grateful to Drs. Mandana Zandian and Jasmine Wang for lab assistance, as well as the Biobank and Translational Research Shared Resource of Cedars-Sinai Cancer. Cartoons in Figs.?8 g and 9 were created with BioRender.com. This work was supported by NCI R01 awards 1R01CA218526 and 1R01CA232574, Cedars-Sinai Development of Prostate Cancer Fund, Cedars-Sinai Precision Health Award, and UCLA CTSI Core Voucher Award [W.Y.] and the Department of Defense (DoD)?Early Investigator Research Award W81XWH-18-1-0476 [Y.Y.].
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123973874&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28340-6
DO - 10.1038/s41467-022-28340-6
M3 - Article
C2 - 35115556
AN - SCOPUS:85123973874
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 669
ER -