Anti-androgen receptor activity of apoptotic CK2 inhibitor CX4945 in human prostate cancer LNCap cells

• Published in: Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (17), p.5470-5474
• Main Authors: Ryu, Byung Jun, Baek, Seung-hwa, Kim, Jiyeon, Bae, Su Jung, Chang, Sung-Youn, Heo, Jung-Nyoung, Lee, Hyuk, Lee, Sang Yeol, Kim, Seong Hwan
• Format: Article
• Language: English
• Subjects: AKT protein; Androgen Antagonists - pharmacology; Androgen receptor; Androgen receptors; Androgens; anticarcinogenic activity; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Casein; Casein kinase II; Casein Kinase II - antagonists & inhibitors; Cell Line, Tumor; CK2; Clinical trials; CX4945; Humans; IAP protein; Male; Medical sciences; Naphthyridines - pharmacology; Pharmacology. Drug treatments; Phosphorylation; Prostate cancer; prostatic neoplasms; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; protein kinases; Receptors, Androgen - metabolism; Transcription; transcription (genetics); Transcription activation; transcriptional activation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.031

CX4945, a potent and selective small molecule inhibitor of CK2, exhibits its anti-cancer activity in LNCap cells via the independent inhibitions of AR and Akt-survivin signalings. Androgen receptor (AR) is crucial for transcriptional signaling in prostate cancers. The anti-cancer activity of protein kinase CK2 (formerly called casein kinase 2)-specific small molecule inhibitors have been reported in several cancers including prostate cancers. The orally available CX4945, a potent and selective small molecule inhibitor of CK2, has advanced into human clinical trials and has exhibited strong anti-tumor activity. The inhibition of CK2 leads to a down-regulation of the AR-dependent transcription, but the functional relevance of CX4945 to AR-dependent transcription in AR-positive LNCap cells has not been studied yet. Our observation of inhibitory effects of CX4945 on the expression or phosphorylation levels of CK2α, Akt and anti-apoptotic molecules including IAP family members agreed with a previous study showing the effect of CK2 inhibition in cancer cells. This study also provides novel information on the impact of CX4945 in the inhibition of AR-dependent transcriptional activation in LNCap cells via its down-regulation. Pharmacologic inhibition experiment revealed that CX4945 could exhibit its anti-cancer activity in LNCap cells via the independent inhibitions of AR and Akt-survivin signalings.