AMPK?2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27.

ABSTRACT: AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism. Interestingly, AMPK?2 knockdown resulted in reduced p27 levels, whereas AMPK?1 suppression did not. To further determine the exact mechanism by which AMPKa2 regulates p27, HTB2 and HT1376 cells were transduced with an shRNA targeting AMPK?2. Stable knockdown of AMPK?2 resulted in increased proliferation and decreased p27 protein. The reduced p27 protein was determined to be dependent upon SKP2. Additionally, loss of AMPK?2 in a xenograft and a chemical carcinogen model of bladder cancer resulted in larger tumors with less p27 protein and high SKP2 levels. Consistent with the regulation observed in the bladder cancer model systems, a comprehensive survey of human primary bladder cancer clinical specimens revealed low levels of AMPK?2 and p27 and high levels of SKP2.These results highlight the contribution of AMPK?2 as a mechanism for controlling bladder cancer growth by regulating proliferation through mTOR suppression and induction of p27 protein levels, thus indicating how AMPK?2 loss may contribute to tumorigenesis. Mol Cancer Res; 14(12); 1182-94. ©2016 AACR.

SUBMITTER: Kopsiaftis S 

PROVIDER: S-EPMC5136331 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other