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.
Highlights
Metastasis accounts for >90% of cancer death [1−3]
Creatine kinase B (CKB) is downregulated in human solid tumors and its lower expression correlates with worse prognosis in prostate cancer patients
We found that CKB inhibits Epithelial-mesenchymal transition (EMT) through post-translationally blocking the activation of AKT that is a critical event for EMT
Summary
Identifying new regulators for cancer metastasis is critical for developing new and effective therapeutics to treat cancer patients and extend their lives. EMT is controlled by both positive and negative regulators [9]. EMT transcription factors (EMTTFs), such as Twist, Twist, Snail, Slug, Zeb and Zeb, are the most well-established regulators of EMT. Other positive EMT regulators include the PI3K/AKT pathways, TGF beta, the hypoxia/HIF pathway, and many others [9−12]. Only a few negative regulators of EMT have been reported, such as the miR-200 family, PTEN and several long noncoding RNAs [12−15]
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