First Author | Kopsiaftis S | Year | 2016 |
Journal | Mol Cancer Res | Volume | 14 |
Issue | 12 | Pages | 1182-1194 |
PubMed ID | 27638620 | Mgi Jnum | J:237853 |
Mgi Id | MGI:5817285 | Doi | 10.1158/1541-7786.MCR-16-0111 |
Citation | Kopsiaftis S, et al. (2016) AMPKalpha2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27. Mol Cancer Res 14(12):1182-1194 |
abstractText | 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, AMPKalpha2 knockdown resulted in reduced p27 levels, whereas AMPKalpha1 suppression did not. To further determine the exact mechanism by which AMPKa2 regulates p27, HTB2 and HT1376 cells were transduced with an shRNA targeting AMPKalpha2. Stable knockdown of AMPKalpha2 resulted in increased proliferation and decreased p27 protein. The reduced p27 protein was determined to be dependent upon SKP2. Additionally, loss of AMPKalpha2 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 AMPKalpha2 and p27 and high levels of SKP2. IMPLICATIONS: These results highlight the contribution of AMPKalpha2 as a mechanism for controlling bladder cancer growth by regulating proliferation through mTOR suppression and induction of p27 protein levels, thus indicating how AMPKalpha2 loss may contribute to tumorigenesis. Mol Cancer Res; 14(12); 1182-94. (c)2016 AACR. |