TY - JOUR
T1 - Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase
AU - Rawat, Chitra
AU - Ben-Salem, Salma
AU - Singh, Nidhi
AU - Chauhan, Gaurav
AU - Rabljenovic, Anja
AU - Vaghela, Vishwa
AU - Venkadakrishnan, Varadha Balaji
AU - Macdonald, Jonathan D.
AU - Dahiya, Ujjwal R.
AU - Ghanem, Yara
AU - Bachour, Salam
AU - Su, Yixue
AU - DePriest, Adam D.
AU - Lee, Sanghee
AU - Muldong, Michelle
AU - Kim, Hyun Tae
AU - Kumari, Sangeeta
AU - Valenzuela, Malyn May
AU - Zhang, Dingxiao
AU - Hu, Qiang
AU - Gomez, Eduardo Cortes
AU - Dehm, Scott M.
AU - Zoubeidi, Amina
AU - Jamieson, Christina A.M.
AU - Nicolas, Marlo
AU - McKenney, Jesse
AU - Willard, Belinda
AU - Klein, Eric A.
AU - Magi-Galluzzi, Cristina
AU - Stauffer, Shaun R.
AU - Liu, Song
AU - Heemers, Hannelore V.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research Inc.. All rights reserved.
PY - 2023/12/15
Y1 - 2023/12/15
N2 - Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2–Skp2–p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.
AB - Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2–Skp2–p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.
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U2 - 10.1158/0008-5472.CAN-23-0883
DO - 10.1158/0008-5472.CAN-23-0883
M3 - Article
C2 - 37801613
AN - SCOPUS:85180012410
SN - 0008-5472
VL - 183
SP - 4142
EP - 4160
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -