CKB Inhibits Epithelial-Mesenchymal Transition and Prostate Cancer Progression by Sequestering and Inhibiting AKT Activation

Authors

Zheng Wang
Mohit Hulsurkar
Lijuan Zhuo
Jinbang Xu
Han Yang
Samira Naderinezhad
Lin Wang
Guoliang Zhang
Nanping Ai
Linna Li
Jeffrey T Chang
Songlin Zhang
Ladan Fazli
Chad J Creighton
Fang Bai
Michael M Ittmann
Martin E Gleave
Wenliang Li

Publication Date

11-1-2021

Journal

Neoplasia

DOI

10.1016/j.neo.2021.09.005

PMID

34706306

PMCID

PMC8551525

PubMedCentral® Posted Date

10-24-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Creatine Kinase, BB Form, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Inbred NOD, Mice, SCID, Prognosis, Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Creatine kinase B (CKB), AKT activation, Epithelial-mesenchymal transition (EMT), Prostate cancer progression and metastasis, Physical sequestration and inhibition of AKT activation

Abstract

Epithelial-mesenchymal transition (EMT) contributes to tumor invasion, metastasis and drug resistance. AKT activation is key in a number of cellular processes. While many positive regulators for either EMT or AKT activation have been reported, few negative regulators are established. Through kinase cDNA screen, we identified brain-type creatine kinase (CKB or BCK) as a potent suppressor for both. As a ubiquitously expressed kinase in normal tissues, CKB is significantly downregulated in several solid cancer types. Lower CKB expression is significantly associated with worse prognosis. Phenotypically, CKB overexpression suppresses, while its silencing promotes, EMT and cell migration, xenograft tumor growth and metastasis of prostate cancer cells. AKT activation is one of the most prominent signaling events upon CKB silencing in prostate cancer cells, which is in line with prostate cancer TCGA data. EMT enhanced by CKB silencing is abolished by AKT inhibition. Mechanistically, CKB interacts with AKT and sequestrates it from activation by mTOR. We further elucidated that an 84aa fragment at C-terminus of CKB protein interacts with AKT's PH domain. Ectopic expression of the 84aa CKB fragment inhibits AKT activation, EMT and cell proliferation. Interestingly, molecular dynamics simulation on crystal structures of AKT and CKB independently demonstrates that AKT's PH domain and CKB's 84aa fragment establish their major interaction interface. In summary, we have discovered CKB as a negative regulator of EMT and AKT activation, revealing a new mode of their regulation . We have also demonstrated that CKB downregulation is a poor prognosticator, which is sufficient to promote prostate cancer progression.

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